Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator Protein and Methods of Use

ABSTRACT

The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/463,019, filed Feb. 24, 2017 and U.S. Provisional Application No. 62/583,237, filed Nov. 8, 2017, both of which are incorporated herein by reference for all purposes.

BACKGROUND OF THE INVENTION Technical Field

This invention relates to compounds that are modulators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, useful in treating diseases and conditions mediated and modulated by CFTR. This invention also relates to compositions containing compounds of the invention, processes for their preparation, and methods of treatment using them.

Description of Related Technology

ABC transporters are a family of homologous membrane transporter proteins regulating the transport of a wide variety of pharmacological agents (for example drugs, xenobiotics, anions, etc.) that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were found to defend malignant cancer cells against chemotherapeutic agents, acting as multidrug resistance proteins (like the MDR1-P glycoprotein, or the multidrug resistance protein, MRP 1). So far, 48 ABC transporters, grouped into 7 families based on their sequence identity and function, have been identified.

ABC transporters provide protection against harmful environmental compounds by regulating a variety of important physiological roles within the body, and therefore represent important potential drug targets for the treatment of diseases associated with transporter defects, outwards cell drug transport, and other diseases in which modulation of ABC transporter activity may be beneficial.

The cAMP/ATP-mediated anion channel, CFTR, is one member of the ABC transporter family commonly associated with diseases, which is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. The activity of CFTR in epithelial cells is essential for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue (Quinton, P. M., 1990. Cystic fibrosis: a disease in electrolyte transport. FASEB J. 4, 2709-2717).

The gene encoding CFTR has been identified and sequenced (Kerem, B., Rommens, J. M., Buchanan, J A, Markiewicz, D., Cox, T. K., Chakravarti, A., Buchwald, M., Tsui, L. C., 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073-1080). CFTR comprises about 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The pair of transmembrane domains is linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.

Cystic fibrosis (CF) is caused by a defect in this gene which induces mutations in CFTR. Cystic fibrosis is the most common fatal genetic disease in humans, and affects 0.04% of white individuals (Bobadilla, J. L., Macek, M., Jr, Fine, J. P., Farrell, P. M., 2002. Cystic fibrosis: a worldwide analysis of CFTR mutations—correlation with incidence data and application to screening. Hum. Mutat. 19, 575-606. doi:10.1002/humu. 10041), for example, in the United States, about one in every 2,500 infants is affected, and up to 10 million people carry a single copy of the defective gene without apparent ill effects; moreover subjects bearing a single copy of the gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea. This effect might explain the relatively high frequency of the CF gene within the population.

In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung infections.

In cystic fibrosis patients, mutations in endogenous respiratory epithelial CFTR fails to confer chloride and bicarbonate permeability to epithelial cells in lung and other tissues, thus leading to reduced apical anion secretion and disruptions of the ion and fluid transport. This decrease in anion transport causes an enhanced mucus and pathogenic agent accumulation in the lung triggering microbial infections that ultimately cause death in CF patients.

Beyond respiratory disease, CF patients also suffer from gastrointestinal problems and pancreatic insufficiency that result in death if left untreated. Furthermore, female subjects with cystic fibrosis suffer from decreased fertility, whilst males with cystic fibrosis are infertile.

A variety of disease causing mutations has been identified through sequence analysis of the CFTR gene of CF chromosomes (Kerem, B., Rommens, J. M., Buchanan, J A, Markiewicz, D., Cox, T. K., Chakravarti, A., Buchwald, M., Tsui, L. C., 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073-1080). ΔF508-CFTR, the most common CF mutation (present in at least 1 allele in 90% of CF patients) and occurring in approximately 70% of the cases of cystic fibrosis, contains a single amino acid deletion of phenylalanine 508. This deletion prevents the nascent protein from folding correctly, which protein in turn cannot exit the endoplasmic reticulum (ER) and traffic to the plasma membrane, and then is rapidly degraded. As a result, the number of channels present in the membrane is far less than in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Indeed, even if ΔF508-CFTR is allowed to reach the cell plasma membrane by low-temperature (27° C.) rescue where it can function as a cAMP-activated chloride channel, its activity is decreased significantly compared with WT-CFTR (Pasyk, E. A., Foskett, J. K., 1995. Mutant (δF508) Cystic Fibrosis Transmembrane Conductance Regulator Cl⁻ Channel Is Functional When Retained in Endoplasmic Reticulum of Mammalian Cells. J. Biol. Chem. 270, 12347-12350).

Other mutations with lower incidence have also been identified that alter the channel regulation or the channel conductance. In case of the channel regulation mutants, the mutated protein is properly trafficked and localized to the plasma membrane but either cannot be activated or cannot function as a chloride channel (e.g. missense mutations located within the nucleotide binding domains), examples of these mutations are G551D, G178R, and G1349D. Mutations affecting chloride conductance have a CFTR protein that is correctly trafficked to the cell membrane but that generates reduced chloride flow (e.g. missense mutations located within the membrane-spanning domain), examples of these mutations are R117H and R334W.

In addition to cystic fibrosis, CFTR activity modulation may be beneficial for other diseases not directly caused by mutations in CFTR, such as, for example, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjögren's syndrome.

COPD is characterized by a progressive and non-reversible airflow limitation, which is due to mucus hypersecretion, bronchiolitis, and emphysema. A potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD could consist in using activators of mutant or wild-type CFTR. In particular, the anion secretion increase across CFTR may facilitate fluid transport into the airway surface liquid to hydrate the mucus and optimize periciliary fluid viscosity. The resulting enhanced mucociliary clearance would help in reducing the symptoms associated with COPD.

Dry eye disease is characterized by a decrease in tear production and abnormal tear film lipid, protein and mucin profiles. Many factors may cause dry eye disease, some of which include age, arthritis, Lasik eye surgery, chemical/thermal burns, medications, allergies, and diseases, such as cystic fibrosis and Sjögren's syndrome. Increasing anion secretion via CFTR could enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye, and eventually improve corneal hydration, thus helping to alleviate dry eye disease associated symptoms. Sjögren's syndrome is an autoimmune disease where the immune system harms moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. The ensuing symptoms, include, dry eye, mouth, and vagina, as well as lung disease. Sjögren's syndrome is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymyositis/dermatomyositis. The cause of the disease is believed to lie in defective protein trafficking, for which treatment options are limited. As a consequence, modulation of CFTR activity may help hydrating the various organs and help to elevate the associated symptoms.

In addition to CF, the defective protein trafficking induced by the ΔF508-CFTR has been shown to be the underlying basis for a wide range of other diseases, in particular diseases where the defective functioning of the endoplasmic reticulum (ER) may either prevent the CFTR protein to exit the cell, and/or the misfolded protein is degraded (Morello, J.-P., Bouvier, M., Petäjä-Repo, U. E., Bichet, D. G., 2000. Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol. Sci. 21, 466-469. doi:10.1016/S0165-6147(00)01575-3; Shastry, B. S., 2003. Neurodegenerative disorders of protein aggregation. Neurochem. Int. 43, 1-7. doi:10.1016/S0197-0186(02)00196-1; Zhang, W., Fujii, N., Naren, A. P., 2012. Recent advances and new perspectives in targeting CFTR for therapy of cystic fibrosis and enterotoxin-induced secretory diarrheas. Future Med. Chem. 4, 329-345. doi:10.4155/fmc.12.1).

A number of genetic diseases are associated with a defective ER processing equivalent to the defect observed with CFTR in CF such as glycanosis CDG type 1, hereditary emphysema (α-1-antitrypsin (PiZ variant)), congenital hyperthyroidism, osteogenesis imperfecta (Type I, II, or IV procollagen), hereditary hypofibrinogenemia (fibrinogen), ACT deficiency (α-1-antichymotrypsin), diabetes insipidus (DI), neurophyseal DI (vasopvessin hormoneN2-receptor), neprogenic DI (aquaporin II), Charcot-Marie Tooth syndrome (peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (APP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's disease, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (prion protein processing defect), Fabry disease (lysosomal α-galactosidase A), Straussler-Scheinker syndrome, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjögren's syndrome.

In addition to up-regulation of the activity of CFTR, anion secretion reduction by CFTR modulators may be beneficial for the treatment of secretory diarrheas, in which epithelial water transport is dramatically increased as a result of secretagogue activated chloride transport. The mechanism involves elevation of cAMP and stimulation of CFTR.

Regardless of the cause, excessive chloride transport is seen in all diarrheas, and results in dehydration, acidosis, impaired growth and death. Acute and chronic diarrheas remain a major medical problem worldwide, and are a significant factor in malnutrition, leading to death in children of less than five years old (5,000,000 deaths/year). Furthermore, in patients with chronic inflammatory bowel disease (IBD) and/or acquired immunodeficiency syndrome (AIDS), diarrhea is a dangerous condition.

Accordingly, there is a need for novel compounds able to modulate CFTR. In particular, the present invention discloses compounds that may act as CFTR modulators for the treatment of cystic fibrosis. The present invention also provides methods for the preparation of these compounds, pharmaceutical compositions comprising these compounds and methods for the treatment of cystic fibrosis by administering the compounds of the invention.

SUMMARY

In one aspect, the invention provides for compounds of Formula (I)

wherein

-   -   A¹ is selected from the group consisting of

-   -   X¹ is N or C(R^(2A));     -   X² is N or C(R^(2B));     -   X³ is N or C(R^(2C));     -   X⁴ is N or C(R^(2D));     -   R¹ is selected from the group consisting of hydrogen, OH, CN,         C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the         R¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy         are optionally substituted with one or more substituents         independently selected from the group consisting of R⁷, OR⁷,         SR⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I;         wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl,         C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered         heterocyclyl are optionally substituted with one or more         substituents independently selected from the group consisting of         C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,         C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the         remaining are independently selected from the group consisting         of hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,         C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; or     -   two of R^(2A), R^(2B), R^(2C), and R^(2D) on adjacent carbons         form a fused ring selected from the group consisting of phenyl,         5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl,         and 4-7 membered heterocyclyl; and the remaining are         independently selected from the group consisting of hydrogen,         R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,         C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein the phenyl, 5-6 membered heteroaryl, C₃-C₇         cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of R⁸, OR⁸,         C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH,         CN, NO₂, F, Cl, Br and I;     -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆         alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆         alkenyl, and C₂-C₆ alkynyl are optionally substituted with one         or more substituents independently selected from the group         consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br         and I; wherein the R³ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl are optionally substituted with one or         more substituents independently selected from the group         consisting of R⁹, OR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂,         C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH,         oxo, CN, NO₂, F, Cl, Br and I;     -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆         alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with         one or more substituents independently selected from the group         consisting of R¹⁰, OR¹⁰, SR¹⁰, NHR¹⁰, N(R¹⁰)₂, NH₂, C(O)OH, OH,         oxo, CN, NO₂, F, Cl, Br and I;     -   R^(5A), R^(5B), R^(5C), and R^(5D) are each independently         selected from the group consisting of hydrogen, C₁-C₆ alkyl,         C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl; wherein the         R^(5A), R^(5B), R^(5C), and R^(5D) C₁-C₆ alkyl, C₂-C₆ alkenyl,         C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with         one or more substituents independently selected from the group         consisting of 6-10 membered aryl, 5-11 membered heteroaryl,         C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered         heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and         I; wherein the R^(5A), R^(5B), R^(5C), and R^(5D) 6-10 membered         aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl are optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo,         CN, NO₂, F, Cl, Br and I; or     -   R^(5A) and R^(5B), together with the carbon atom to which they         are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7         membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic         cycloalkyl and the 4-7 membered monocyclic heterocycle are each         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R^(5C) and R^(5D) are each independently selected from the group         consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆         alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R^(5C) and R^(5D) C₁-C₆         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are         optionally substituted with one or more substituents         independently selected from the group consisting of 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆         thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5C)         and R^(5D) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; or     -   R^(5A) and R^(5B) are each independently selected from the group         consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆         alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R^(5A) and R^(5B) C₁-C₆         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are         optionally substituted with one or more substituents         independently selected from the group consisting of 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆         thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5A)         and R^(5B) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R^(5C) and R^(5D), together with the carbon atom to which they         are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7         membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic         cycloalkyl and the 4-7 membered monocyclic heterocycle are each         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R^(6A), R^(6B), R^(6C), and R^(6D) are each independently         hydrogen;     -   R⁷, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆         alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁷ 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and         I;     -   R⁸, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹¹, OR¹¹,         C(O)OR¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl is optionally substituted with one or more         substituents independently selected from the group consisting of         R¹², OR¹², C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, oxo, CN,         NO₂, F, Cl, Br and I;     -   R⁹, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁹         C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally         substituted with one or more substituents independently selected         from the group consisting of R¹³, OR¹³, SR¹³, C(O)R¹³, NHR¹³,         N(R¹³)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein each R⁹         6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are         optionally substituted with one or more substituents         independently selected from the group consisting of R¹⁴, OR¹⁴,         C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴, SO₂R¹⁴, NHR¹⁴, N(R¹⁴)₂, NH₂,         C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R¹⁰, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹⁰ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of OH, oxo, CN,         NO₂, F, Cl, Br and I; wherein each R¹⁰ C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, cycloalkenyl, and         4-12 membered heterocyclyl is optionally substituted with one or         more substituents independently selected from the group         consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered         heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R¹¹, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered         aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁         cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹         C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one         or more substituents independently selected from the group         consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each         R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered         heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, F, Cl, Br and I;     -   R¹², at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered         aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁         cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹²         C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one         or more substituents independently selected from the group         consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each         R¹² C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered         heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, F, Cl, Br and I;     -   R¹³, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of OH, oxo, CN,         NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, cycloalkyl, C₄-C₁₁ cycloalkenyl, and         4-12 membered heterocyclyl is optionally substituted with one or         more substituents independently selected from the group         consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered         heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R¹⁴, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered         heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   with the proviso that R³ is not methyl;     -   with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D)         are each hydrogen, R¹ is not hydrogen;     -   with the proviso that, when R³ is naphthyl, R^(2C) is not         4-(1-methylethyl)phenoxy; and     -   with the proviso that, when R¹ is C₁-alkyl, R³ is not         3-pyridinyl or 4-cyanobenzyl.

Another aspect of the invention relates to pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier. Such compositions can be administered in accordance with a method of the invention, typically as part of a therapeutic regimen for treatment or prevention of conditions and disorders related to Cystic Fibrosis Transmembrane Conductance Regulator activity. In a particular aspect, the pharmaceutical compositions may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of cystic fibrosis.

Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

Yet another aspect of the invention relates to a method for treating, or preventing conditions and disorders related to Cystic Fibrosis Transmembrane Conductance Regulator activity in mammals. More particularly, the method is useful for treating or preventing conditions and disorders related to cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, or chronic obstructive airway disease. Accordingly, the compounds and compositions of the invention are useful as a medicament for treating or preventing Cystic Fibrosis Transmembrane Conductance Regulator modulated disease.

The compounds, compositions comprising the compounds, methods for making the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are further described herein.

In a particular aspect, the compounds of the invention are provided for use in the treatment of cystic fibrosis. In a particular aspect, the compounds of the invention are provided for use in the treatment of cystic fibrosis caused by class I, II, III, IV, V, and/or VI mutations.

The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier for use in medicine. In a particular aspect, the pharmaceutical composition is for use in the treatment of cystic fibrosis.

These and other objects of the invention are described in the following paragraphs. These objects should not be deemed to narrow the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Described herein are compounds of Formula (I)

wherein A¹, R³, and R⁴ are defined above in the Summary and below in the Detailed Description. Further, compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also included.

Compounds included herein may contain one or more variable(s) that occur more than one time in any substituent or in the formulae herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated from a reaction mixture.

Compounds included herein may contain one or more variable(s) that occur more than one time in any substituent or in the formulae herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated from a reaction mixture.

Definitions

It is noted that, as used in this specification and the intended claims, the singular form “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a single compound as well as one or more of the same or different compounds; reference to “a pharmaceutically acceptable carrier” means a single pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers, and the like.

As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond. The term “C₂-C₆ alkenyl” means an alkenyl group containing 2-6 carbon atoms. Non-limiting examples of C₂-C₆ alkenyl include buta-1,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.

The term “C₁-C₆ alkoxy” as used herein, means a C₁-C₆ alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term “alkyl” as used herein, means a saturated, straight or branched hydrocarbon chain radical. In some instances, the number of carbon atoms in an alkyl moiety is indicated by the prefix “C_(x)-C_(y)”, wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, “C₁-C₆ alkyl” means an alkyl substituent containing from 1 to 6 carbon atoms and “C₁-C₃ alkyl” means an alkyl substituent containing from 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, and 1,2,2-trimethylpropyl. The terms “alkyl,” “C₁-C₆ alkyl,” “C₁-C₄ alkyl,” and “C₁-C₃ alkyl” used herein are unsubstituted, unless otherwise indicated.

The term “alkylene” or “alkylenyl” means a divalent radical derived from a straight or branched, saturated hydrocarbon chain, for example, of 1 to 10 carbon atoms or of 1 to 6 carbon atoms (C₁-C₆ alkylenyl) or of 1 to 4 carbon atoms or of 1 to 3 carbon atoms (C₁-C₃ alkylenyl) or of 2 to 6 carbon atoms (C₂-C₆ alkylenyl). Examples of C₁-C₆ alkylenyl include, but are not limited to, —CH₂—, —CH₂CH₂—, —C(CH₃)₂—CH₂CH₂CH₂—, —C(CH₃)₂—CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “C₂-C₆ alkynyl” as used herein, means a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of C₂-C₆ alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “C₃-C₁₁ cycloalkyl” as used herein, means a hydrocarbon ring radical containing 3-11 carbon atoms, zero heteroatoms, and zero double bonds. The C₃-C₁₁ cycloalkyl group may be a single-ring (monocyclic) or have two or more rings (polycyclic or bicyclic). Monocyclic cycloalkyl groups typically contain from 3 to 8 carbon ring atoms (C₃-C₁₁ monocyclic cycloalkyl), and even more typically 3-6 carbon ring atoms (C₃-C₆ monocyclic cycloalkyl). Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups contain two or more rings, and bicyclic cycloalkyls contain two rings. In certain embodiments, the polycyclic cycloalkyl groups contain 2 or 3 rings. The rings within the polycyclic and the bicyclic cycloalkyl groups may be in a bridged, fused, or spiro orientation, or combinations thereof. In a spirocyclic cycloalkyl, one atom is common to two different rings. Examples of a spirocyclic cycloalkyl include spiro[2.5]octanyl and spiro[4.5]decanyl. In a bridged cycloalkyl, the rings share at least two non-adjacent atoms. Examples of bridged cycloalkyls include, but are not limited to bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, and bicyclo[4.2.1]nonyl, tricyclo[3.3.1.0^(3,7)]nonyl (octahydro-2,5-methanopentalenyl or noradamantyl), tricyclo[3.3.1.1^(3,7)]decyl (adamantyl), and tricyclo[4.3.1.1^(3,8)]undecyl (homoadamantyl). In a fused ring cycloalkyl, the rings share one common bond. Examples of fused-ring cycloalkyl include, but not limited to, decalin (decahydronaphthyl), bicyclo[3.1.0]hexanyl, and bicyclo[2.2.0]octyl.

The term “C₃-C₆ cycloalkyl” as used herein, means a hydrocarbon ring radical containing 3-6 carbon atoms, zero heteroatoms, and zero double bonds. The C₃-C₆ cycloalkyl group may be a single-ring (monocyclic) or have two rings (bicyclic).

The term “C₄-C₁₁ cycloalkenyl” as used herein, means a non-aromatic hydrocarbon ring radical containing 4-11 carbon atoms, zero heteroatoms, and one or more double bonds. The C₄-C₁₁ cycloalkenyl group may be a single-ring (monocyclic) or have two or more rings (polycyclic or bicyclic). Examples of monocyclic cycloalkenyl include cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctenyl, and cyclooctadienyl. Examples of bicyclic cycloalkenyl include bicyclo[2.2.1]hept-2-enyl.

The term “C₄-C₈ monocyclic cycloalkenyl” as used herein, means cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptadienyl, cyclooctenyl, and cyclooctadienyl.

The term “C₄-C₇ monocyclic cycloalkenyl” as used herein, means cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cycloheptyl.

The term “halo” or “halogen” as used herein, means Cl, Br, I, and F.

The term “haloalkyl” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. The term “C₁-C₆ haloalkyl” means a C₁-C₆ alkyl group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen. The term “C₁-C₃ haloalkyl” means a C₁-C₃ alkyl group, as defined herein, in which one, two, three, four, or five hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, and trifluoropropyl.

The term “4-12 membered heterocyclyl” as used herein, means a hydrocarbon ring radical of 4-12 carbon ring atoms wherein at least one carbon atom is replaced by a heteroatom(s) independently selected from the group consisting of O, N, and S. The 4-12 membered heterocycle ring may be a single ring (monocyclic) or have two or more rings (bicyclic or polycyclic). In certain embodiments, the monocyclic heterocycle is a four-, five-, six-, seven-, or eight-membered hydrocarbon ring wherein at least one carbon ring atom is replaced by a heteroatom(s) independently selected from the group consisting of O, N, and S. In certain embodiments, the monocyclic heterocycle is a 4-7 membered hydrocarbon ring wherein at least one carbon ring atom is replaced by a heteroatom(s). A four-membered monocyclic heterocycle contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. A five-membered monocyclic heterocycle contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of five-membered monocyclic heterocycles include those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N; or 1 O and 2 N. Non limiting examples of 5-membered monocyclic heterocyclic groups include 1,3-dioxolanyl, tetrahydrofuranyl, dihydropyranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl, imidazolidinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, thiazolinyl, and thiazolidinyl. A six-membered monocyclic heterocycle contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of six-membered monocyclic heterocycles include those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N. Examples of six-membered monocyclic heterocycles include dihydropyranyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,4-dithianyl, hexahydropyrimidine, morpholinyl, 1,4-dihydropyridinyl, piperazinyl, piperidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl, and trithianyl. Seven- and eight-membered monocyclic heterocycles contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, 1,4-diazepanyl, dihydropyranyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxazepanyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl. Polycyclic heterocycle groups contain two or more rings, and bicyclic heterocycles contain two rings. In certain embodiments, the polycyclic heterocycle groups contain 2 or 3 rings. The rings within the polycyclic and the bicyclic heterocycle groups may be in a bridged, fused, or spiro orientation, or combinations thereof. In a spirocyclic heterocycle, one atom is common to two different rings. Non limiting examples of the spirocyclic heterocycle include 6-oxaspiro[2.5]octanyl, 2-azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.5]octyl, 2-azaspiro[3.5]nonyl, 2-azaspiro[3.4]octyl, 3-azaspiro[5.5]undecyl, 5-azaspiro[3.4]octyl, 2-oxaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 6-oxa-2-azaspiro[3.4]octyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 8-azaspiro[4.5]decyl, 1-oxa-7-azaspiro[4.4]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl, 1-oxa-4,9-diazaspiro[5.5]undecyl, 2-oxa-7-azaspiro[3.5]nonyl, 5-oxa-2-azaspiro[3.5]nonyl, 6-oxa-2-azaspiro[3.5]nonyl, 7-oxa-2-azaspiro[3.5]nonyl, 8-oxa-2-azaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,3,8-triazaspiro[4.5]decyl. In a fused ring heterocycle, the rings share one common bond. Examples of fused bicyclic heterocycles are a 4-6 membered monocyclic heterocycle fused to a phenyl group, or a 4-6 membered monocyclic heterocycle fused to a C₃-C₆ monocyclic cycloalkyl, or a 4-6 membered monocyclic heterocycle fused to a C₄-C₇ monocyclic cycloalkenyl, or a 4-6 membered monocyclic heterocycle fused to a 4-7 membered monocyclic heterocycle. Examples of fused bicyclic heterocycles include, but are not limited to, 1,2-dihydrophthalazinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, chromanyl, chromenyl, isochromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, isoindolinyl, 2,3-dihydrobenzo[b]thienyl, hexahydro-1H-cyclopenta[c]furanyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexyl, benzopyranyl, benzothiopyranyl, indolinyl, decahydropyrrolo[3,4-b]azepinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydro-1H-indolyl, 3,4-dihydroisoquinolin-2(1H)-yl, 2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl, hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, hexahydrocyclopenta[c]pyrrol-3a(1H)-yl, hexahydro-1H-oxazolo[3,4-a]pyrazinyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydroimidazo[1,5-a]pyrazinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, and octahydropyrrolo[3,4-c]pyrrolyl. In a bridged heterocycle, the rings share at least two non-adjacent atoms. Examples of such bridged heterocycles include, but are not limited to, 8-oxabicyclo[3.2.1]octanyl, 7-oxabicyclo[2.2.1]heptanyl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), 8-azabicyclo[3.2.1]oct-8-yl, octahydro-2,5-epoxypentalene, 8-oxa-3-azabicyclo[3.2.1]octyl, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane (1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.1^(3,7)]decane). The nitrogen and sulfur heteroatoms in the heterocycle rings may optionally be oxidized (e.g. 1,1-dioxidotetrahydrothienyl, 1,1-dioxido-1,2-thiazolidinyl, 1,1-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally be quaternized. Non limiting examples of the polycyclic heterocycle include 6,7-dihydro-[1,3]dioxolo[4,5-f]benzofuranyl.

The term “5-11 membered heteroaryl” as used herein, means a monocyclic heteroaryl and a bicyclic heteroaryl. The “5-6 membered heteroaryl” is a five- or six-membered ring. The five-membered ring contains two double bonds. The five membered ring may contain one heteroatom selected from O or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or one sulfur atom. The six-membered ring contains three double bonds and one, two, three or four nitrogen atoms. Examples of 5-6 membered monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridazinonyl, pyridinonyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a C₃-C₆ monocyclic cycloalkyl, or a monocyclic heteroaryl fused to C₄-C₇ monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a 4-7 membered monocyclic heterocycle. Representative examples of bicyclic heteroaryl groups include, but are not limited to, 4H-furo[3,2-b]pyrrolyl, benzofuranyl, benzothienyl, benzoisoxazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl, 2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl, 6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl, 6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and 5,6,7,8-tetrahydroquinolin-5-yl. The nitrogen atom in the heteroaryl rings may optionally be oxidized and may optionally be alkylated.

The term “6-10 membered aryl”, as used herein, means a hydrocarbon ring radical containing 6-10 carbon atoms, zero heteroatoms, and one or more aromatic rings. The 6-10 membered aryl group may be a single-ring (monocyclic) or have two rings (bicyclic). The bicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl. Representative examples of 6-10 membered aryl groups include, but are not limited to, phenyl, indenyl, tetrahydronaphthalenyl, dihydroindenyl (indanyl), naphthyl, and the like.

The aryls, the cycloalkyls, the cycloalkenyls, the heterocycles, and the heteroaryls, including the exemplary rings, are optionally substituted unless otherwise indicated; and are attached to the parent molecular moiety through any substitutable atom contained within the ring system.

The term “heteroatom” as used herein, means a nitrogen, oxygen, and sulfur.

The term “oxo” as used herein, means a=O group.

The term “radiolabel” means a compound of the invention in which at least one of the atoms is a radioactive atom or a radioactive isotope, wherein the radioactive atom or isotope spontaneously emits gamma rays or energetic particles, for example alpha particles or beta particles, or positrons. Examples of such radioactive atoms include, but are not limited to, ³H (tritium), ¹⁴C, ¹¹C, ¹⁵O, ¹⁸F, ³⁵S, ¹²³I, and ¹²⁵I.

A moiety is described as “substituted” when a non-hydrogen radical is in the place of hydrogen radical of any substitutable atom of the moiety. Thus, for example, a substituted heterocycle moiety is a heterocycle moiety in which at least one non-hydrogen radical is in the place of a hydrogen radical on the heterocycle. It should be recognized that if there are more than one substitution on a moiety, each non-hydrogen radical may be identical or different (unless otherwise stated).

If a moiety is described as being “optionally substituted,” the moiety may be either (1) not substituted or (2) substituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.

The terms “treat”, “treating”, and “treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms. In certain embodiments, “treat,” “treating,” and “treatment” refer to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treat”, “treating”, and “treatment” refer to modulating the disease or disorder, either physically (for example, stabilization of a discernible symptom), physiologically (for example, stabilization of a physical parameter), or both. In a further embodiment, “treat”, “treating”, and “treatment” refer to slowing the progression of the disease or disorder.

The terms “prevent”, “preventing”, and “prevention” refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, “prevent”, “preventing” and “prevention” also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring or developing a disease or disorder.

The phrase “therapeutically effective amount” means an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to prevent the development of or to alleviate to some extent one or more of the symptoms of the condition or disorder being treated when administered alone or in conjunction with another therapeutic agent for treatment in a particular subject or subject population. The “therapeutically effective amount” may vary depending on the compound, the disease and its severity, and the age, weight, health, etc., of the subject to be treated. For example in a human or other mammal, a therapeutically effective amount may be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and subject being treated.

The term “subject” is defined herein to refer to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, pigs, horses, dogs, cats, rabbits, rats, mice and the like. In one embodiment, the subject is a human. The terms “human,” “patient,” and “subject” are used interchangeably herein.

The term “one or more” refers to one to eight. In one embodiment it refers to one to eight. In one embodiment it refers to one to seven. In one embodiment it refers to one to six. In one embodiment it refers to one to five. In one embodiment it refers to one to four. In one embodiment it refers to one or three. In another embodiment it refers to one to three. In a further embodiment it refers to one to two. In yet other embodiment it refers to two. In yet other further embodiment it refers to one.

As used herein, “Class I mutation(s)” refers to mutations which interfere with protein synthesis. They result in the introduction of a premature signal of termination of translation (stop codon) in the mRNA. The truncated CFTR proteins are unstable and rapidly degraded, so, the net effect is that there is no protein at the apical membrane. In particular, Class I mutation(s) refers to p.Gly542X (G542X), W1282X, c.489+1G>T (621+1G>T), or c.579+1G>T (711+1G>T) mutation. More particularly, Class I mutation(s) refers to G542X; or W1282X mutations.

As used herein, “Class II mutation(s)” refers to mutations which affect protein maturation. These lead to the production of a CFTR protein that cannot be correctly folded and/or trafficked to its site of function on the apical membrane. In particular, Class II mutation(s) refers to p.Phe508del (F508del), p.Ile507del, or p.Asn1303Lys (N1303K) mutations. More particularly, Class II mutation(s) refers to F508del or N1303K mutations.

As used herein, “Class III mutation(s)” refers to mutations which alter the regulation of the CFTR channel. The mutated CFTR protein is properly trafficked and localized to the plasma membrane but cannot be activated, or it cannot function as a chloride channel. In particular, Class III mutation(s) refers to p.Gly551Asp (G551D), G551S, R553G, G1349D, S1251N, G178R, S549N mutations. More particularly, Class III mutation(s) refers to G551D, R553G, G1349D, S1251N, G178R, or S549N mutations.

As used herein, “Class IV mutation(s)” refers to mutations which affect chloride conductance. The CFTR protein is correctly trafficked to the cell membrane but generates reduced chloride flow or a “gating defect” (most are missense mutations located within the membrane-spanning domain). In particular, Class IV mutation(s) refers to p.Arg117His (R117H), R347P, or p.Arg334Trp (R334W) mutations.

As used herein, “Class V mutation(s)” refers to mutations which reduce the level of normally functioning CFTR at the apical membrane or result in a “conductance defect” (for example partially aberrant splicing mutations or inefficient trafficking missense mutations). In particular, Class V mutation(s) refers to c.1210-12T[5] (5T allele), c.S3140-26A>G (3272-26A>G), c.3850-2477C>T (3849+10kb C>T) mutations.

As used herein, “Class VI mutation(s)” refers to mutations which decrease the stability of the CFTR which is present or which affect the regulation of other channels, resulting in inherent instability of the CFTR protein. In effect, although functional, the CFTR protein is unstable at the cell surface and it is rapidly removed and degraded by cell machinery. In particular, Class VI mutation(s) refers to Rescued F508del, 120del23, N287Y, 4326dellTC, or 4279insA mutations. More particularly, Class VI mutation(s) refers to Rescued F508del mutations.

Compounds

Compounds of the invention are described herein.

Particular values of variable groups are as follows. Such values may be used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter.

Formula (I)

One embodiment pertains to compounds of Formula (I), or a pharmaceutically acceptable salt thereof,

wherein

-   -   A¹ is selected from the group consisting of

-   -   X¹ is N or C(R^(2A));     -   X² is N or C(R^(2B));     -   X³ is N or C(R^(2C));     -   X⁴ is N or C(R^(2D));     -   R¹ is selected from the group consisting of hydrogen, OH, CN,         C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the         R¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy         are optionally substituted with one or more substituents         independently selected from the group consisting of R⁷, OR⁷,         SR⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I;         wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl,         C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered         heterocyclyl are optionally substituted with one or more         substituents independently selected from the group consisting of         C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,         C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the         remaining are independently selected from the group consisting         of hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,         C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; or     -   two of R^(2A), R^(2B), R^(2C), and R^(2D) a on adjacent carbons         form a fused ring selected from the group consisting of phenyl,         5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl,         and 4-7 membered heterocyclyl; and the remaining are         independently selected from the group consisting of hydrogen,         R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,         C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein the phenyl, 5-6 membered heteroaryl, C₃-C₇         cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of R⁸, OR⁸,         C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH,         CN, NO₂, F, Cl, Br and I;     -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆         alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆         alkenyl, and C₂-C₆ alkynyl are optionally substituted with one         or more substituents independently selected from the group         consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br         and I; wherein the R³ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl are optionally substituted with one or         more substituents independently selected from the group         consisting of R⁹, OR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂,         C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH,         oxo, CN, NO₂, F, Cl, Br and I;     -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆         alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with         one or more substituents independently selected from the group         consisting of R¹⁰, OR¹⁰, SR¹⁰, NHR¹⁰, N(R¹⁰)₂, NH₂, C(O)OH, OH,         oxo, CN, NO₂, F, Cl, Br and I;     -   R^(5A), R^(5B), R^(5C), and R^(5D) are each independently         selected from the group consisting of hydrogen, C₁-C₆ alkyl,         C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl; wherein the         R^(5A), R^(5B), R^(5C), and R^(5D) C₁-C₆ alkyl, C₂-C₆ alkenyl,         C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with         one or more substituents independently selected from the group         consisting of 6-10 membered aryl, 5-11 membered heteroaryl,         C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered         heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and         I; wherein the R^(5A), R^(5B), R^(5C), and R^(5D) 6-10 membered         aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl are optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo,         CN, NO₂, F, Cl, Br and I; or     -   R^(5A) and R^(5B), together with the carbon atom to which they         are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7         membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic         cycloalkyl and the 4-7 membered monocyclic heterocycle are each         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R^(5C) and R^(5D) are each independently selected from the group         consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆         alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R^(5C) and R^(5D) C₁-C₆         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are         optionally substituted with one or more substituents         independently selected from the group consisting of 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆         thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5C)         and R^(5D) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; or     -   R^(5A) and R^(5B) are each independently selected from the group         consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆         alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R^(5A) and R^(5B) C₁-C₆         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are         optionally substituted with one or more substituents         independently selected from the group consisting of 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆         thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5A)         and R^(5B) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R^(5C) and R^(5D), together with the carbon atom to which they         are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7         membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic         cycloalkyl and the 4-7 membered monocyclic heterocycle are each         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R^(6A), R^(6B), R^(6C), and R^(6D) are each independently         hydrogen;     -   R⁷, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆         alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁷ 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and         I;     -   R⁸, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹¹, OR¹¹,         C(O)OR¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl is optionally substituted with one or more         substituents independently selected from the group consisting of         R¹², OR¹², C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, oxo, CN,         NO₂, F, Cl, Br and I;     -   R⁹, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹³, OR¹³,         SR¹³, C(O)R¹³, NHR¹³, N(R¹³)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein each R⁹ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl are optionally substituted with one or         more substituents independently selected from the group         consisting of R¹⁴, OR¹⁴, C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴, SO₂R¹⁴,         NHR¹⁴, N(R¹⁴)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R¹⁰, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹⁰ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of OH, oxo, CN,         NO₂, F, Cl, Br and I; wherein each R¹⁰ C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6         membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R¹¹, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered         aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁         cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹         C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one         or more substituents independently selected from the group         consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each         R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered         heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, F, Cl, Br and I;     -   R¹², at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered         aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁         cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹²         C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one         or more substituents independently selected from the group         consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each         R¹² C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered         heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, F, Cl, Br and I;     -   R¹¹, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of OH, oxo, CN,         NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6         membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R¹⁴, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered         heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   with the proviso that R³ is not methyl;     -   with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D)         are each hydrogen, R¹ is not hydrogen;     -   with the proviso that, when R³ is naphthyl, R^(2C) is not         4-(1-methylethyl)phenoxy; and     -   with the proviso that, when R¹ is C₁-alkyl, R³ is not         3-pyridinyl or 4-cyanobenzyl.

One embodiment pertains to a compound of formula (I)

wherein

-   -   A¹ is selected from the group consisting of

-   -   R¹ is selected from the group consisting of hydrogen, OH, CN,         C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the         R¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy         are optionally substituted with one or more substituents         independently selected from the group consisting of R⁷, OR⁷,         SR⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I;         wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl,         C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered         heterocyclyl are optionally substituted with one or more         substituents independently selected from the group consisting of         C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,         C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the         remaining are independently selected from the group consisting         of hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,         C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; or     -   two of R^(2A), R^(2B), R^(2C), and R^(2D) on adjacent carbons         form a fused ring selected from the group consisting of phenyl,         5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl,         and 4-7 membered heterocyclyl; and the remaining are         independently selected from the group consisting of hydrogen,         R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,         C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein the phenyl, 5-6 membered heteroaryl, C₃-C₇         cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of R⁸, OR⁸,         C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH,         CN, NO₂, F, Cl, Br and I;     -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆         alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆         alkenyl, and C₂-C₆ alkynyl are optionally substituted with one         or more substituents independently selected from the group         consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br         and I; wherein the R³ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl are optionally substituted with one or         more substituents independently selected from the group         consisting of R⁹, OR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂,         C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH,         oxo, CN, NO₂, F, Cl, Br and I;     -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆         alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with         one or more substituents independently selected from the group         consisting of R¹⁰, OR¹⁰, SR¹⁰, NHR¹⁰, N(R¹⁰)₂, NH₂, C(O)OH, OH,         oxo, CN, NO₂, F, Cl, Br and I;     -   R^(5A), R^(5B), R^(5C), and R^(5D) are each independently         selected from the group consisting of hydrogen, C₁-C₆ alkyl,         C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl; wherein the         R^(5A), R^(5B), R^(5C), and R^(5D) C₁-C₆ alkyl, C₂-C₆ alkenyl,         C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with         one or more substituents independently selected from the group         consisting of 6-10 membered aryl, 5-11 membered heteroaryl,         C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered         heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and         I; wherein the R^(5A), R^(5B), R^(5C), and R^(5D) 6-10 membered         aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl are optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo,         CN, NO₂, F, Cl, Br and I; or     -   R^(5A) and R^(5B), together with the carbon atom to which they         are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7         membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic         cycloalkyl and the 4-7 membered monocyclic heterocycle are each         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R^(5C) and R^(5D) are each independently selected from the group         consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆         alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R^(5C) and R^(5D) C₁-C₆         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are         optionally substituted with one or more substituents         independently selected from the group consisting of 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆         thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5C)         and R^(5D) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; or     -   R^(5A) and R^(5B) are each independently selected from the group         consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆         alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R^(5A) and R^(5B) C₁-C₆         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are         optionally substituted with one or more substituents         independently selected from the group consisting of 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆         thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5A)         and R^(5B) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R^(5C) and R^(5D), together with the carbon atom to which they         are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7         membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic         cycloalkyl and the 4-7 membered monocyclic heterocycle are each         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R^(6A), R^(6B), R^(6C), and R^(6D) are each independently         hydrogen;     -   R⁷, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆         alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁷ 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and         I;     -   R⁸, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹¹, OR¹¹,         C(O)OR¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl is optionally substituted with one or more         substituents independently selected from the group consisting of         R¹², OR¹², C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, oxo, CN,         NO₂, F, Cl, Br and I;     -   R⁹, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹³, OR¹³,         SR¹³, C(O)R¹³, NHR¹³, N(R¹³)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein each R⁹ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl are optionally substituted with one or         more substituents independently selected from the group         consisting of R¹⁴, OR¹⁴, C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴, SO₂R¹⁴,         NHR¹⁴, N(R¹⁴)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R¹⁰, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹⁰ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of OH, oxo, CN,         NO₂, F, Cl, Br and I; wherein each R¹⁰ C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6         membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R¹¹, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered         aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁         cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹         C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one         or more substituents independently selected from the group         consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each     -   R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered         heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, F, Cl, Br and I;     -   R¹², at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered         aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁         cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹²         C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one         or more substituents independently selected from the group         consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each         R¹² C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered         heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, F, Cl, Br and I;     -   R¹³, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of OH, oxo, CN,         NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6         membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R¹⁴, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered         heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   with the proviso that R³ is not methyl;     -   with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D)         are each hydrogen, R¹ is not hydrogen;     -   with the proviso that, when R³ is naphthyl, R^(2C) is not         4-(1-methylethyl)phenoxy; and     -   with the proviso that, when R¹ is C₁-alkyl, R³ is not         3-pyridinyl or 4-cyanobenzyl.

In one embodiment of Formula (I), A¹ is selected from the group consisting of

In another embodiment of Formula (I), A¹ is

In another embodiment of Formula (I), A¹ is

In another embodiment of Formula (I), A¹ is

In another embodiment of Formula (I), A¹ is

In another embodiment of Formula (I), A¹ is

In one embodiment of Formula (I), X¹ is N or C(R^(2A)). In another embodiment of Formula (I), X¹ is N. In another embodiment of Formula (I), X¹ is C(R^(2A)).

In one embodiment of Formula (I), X² is N or C(R^(2B)). In another embodiment of Formula (I), X² is N. In another embodiment of Formula (I), X² is C(R^(2B)).

In one embodiment of Formula (I), X³ is N or C(R^(2C)). In another embodiment of Formula (I), X³ is N. In another embodiment of Formula (I), X³ is C(R^(2C)).

In one embodiment of Formula (I), X⁴ is N or C(R^(2D)). In another embodiment of Formula (I), X⁴ is N. In another embodiment of Formula (I), X⁴ is C(R^(2D)).

In one embodiment of Formula (I), X¹ is C(R^(2A)); X² is C(R^(2B)); X³ is C(R^(2C)); and X⁴ is C(R^(2D)).

In one embodiment of Formula (1), A¹ is selected from the group consisting of

In another embodiment of Formula (I), A¹ is

In another embodiment of Formula (I), A¹ is

In another embodiment of Formula (I), A¹ is

In another embodiment of Formula (I), A¹ is

In another embodiment of Formula (I), A¹ is

In one embodiment of Formula (I), R¹ is selected from the group consisting of hydrogen, OH, CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, SR⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (I), R¹ is selected from the group consisting of hydrogen, CN, and C₁-C₆ alkyl; wherein the R¹ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, N(R⁷)₂, C(O)OH, OH, and CN. In another embodiment of Formula (I), R¹ is hydrogen. In another embodiment of Formula (I), R¹ is CN. In another embodiment of Formula (I), R¹ is C₁-C₆ alkyl; which is unsubstituted. In another embodiment of Formula (I), R¹ is hydrogen or C₁-C₆ alkyl; which is unsubstituted. In another embodiment of Formula (I), R¹ is C₁-C₆ alkyl; wherein the R¹ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, N(R⁷)₂, C(O)OH, OH, and CN.

In one embodiment of Formula (I), one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D) are each hydrogen, R¹ is not hydrogen. In another embodiment of Formula (I), one of R^(2A), R^(2B), R^(2C) and R^(2D) is hydrogen, and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, F, Cl, and Br; with the proviso that, when R^(2A), R^(2B), R^(2C) and R^(2D) are each hydrogen, R¹ is not hydrogen. In another embodiment of Formula (I), R^(2A), R^(2B), R^(2C), and R^(2D) are hydrogen; with the proviso that R¹ is not hydrogen.

In one embodiment of Formula (I), two of R^(2A), R^(2B), R^(2C) and R^(2D) on adjacent carbons form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein the phenyl, 5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (I), R^(2C) and R^(2D) form a 4-7 membered heterocyclyl; and R^(2A) and R^(2B) are independently hydrogen.

In one embodiment of Formula (I), R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (I), R³ is selected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy and phenyl; wherein the R³ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (I), R³ is C₁-C₆ alkyl; wherein the R³ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy and phenyl. In another embodiment of Formula (I), R³ is 6-10 membered aryl; wherein the R³ 6-10 membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (I), R³ is 5-11 membered heteroaryl; wherein the R³ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (I), R³ is C₃-C₁₁ cycloalkyl; wherein the R³ C₃-C₁₁ cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (I), R³ is 4-12 membered heterocyclyl; wherein the R³ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br.

In one embodiment of Formula (I), R⁴ is selected from the group consisting of hydrogen and C₁-C₆ alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹⁰, OR¹⁰, SR¹⁰, NHR¹⁰, N(R¹⁰)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (I), R⁴ is hydrogen. In another embodiment of Formula (I), R⁴ is C₁-C₆ alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with one or more R¹⁰.

In one embodiment of Formula (I), R^(5A), R^(5B), R^(5C), and R^(5D) are each independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R^(5A), R^(5B), R^(5C), and R^(5D) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5A), R^(5B), R^(5C), and R^(5D) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; or R^(5A) and R^(5B), together with the carbon atom to which they are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic cycloalkyl and the 4-7 membered monocyclic heterocycle are each optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and R^(5C) and R^(5D) are each independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R^(5C) and R^(5D) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5C) and R^(5D) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; or R^(5A) and R^(5B) are each independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R^(5A) and R^(5B) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5A) and R^(5B) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and R^(5C) and R^(5D), together with the carbon atom to which they are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic cycloalkyl and the 4-7 membered monocyclic heterocycle are each optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (I), R^(5A), R^(5B), R^(5C), and R^(5D) are each independently hydrogen. In another embodiment of Formula (I), R^(5A), R^(5B), R^(5C), and R^(5D) are each independently C₁-C₆ alkyl.

In one embodiment of Formula (I), R^(6A), R^(6B), R^(6C), and R^(6D) are each independently hydrogen.

In one embodiment of Formula (I), R⁷, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁷ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (I), R⁷, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁷ C₁-C₆ alkyl is optionally substituted with one or more C₁-C₆ alkoxy; wherein each R⁷ 5-11 membered heteroaryl and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆ haloalkyl, F, and Cl.

In one embodiment of Formula (I), R⁸, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹¹, OR¹¹, C(O)OR¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹², OR¹², C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (I), R⁸, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁸ C₁-C₆ alkyl and C₂-C₆ alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹¹, OR¹¹, C(O)OR¹¹, OH, and F; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹², OR¹², N(R¹²)₂, and F.

In one embodiment of Formula (I), R⁹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹³, OR¹³, SR¹³, C(O)R¹³, NHR¹³, N(R¹³)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴, OR¹⁴, C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴, SO₂R¹⁴, NHR¹⁴, N(R¹⁴)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (I), R⁹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹³, OR¹³, C(O)R¹³, N(R¹³)₂, OH, F, and Cl; wherein each R⁹ 6-10 membered aryl and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴, oxo, and F.

In one embodiment of Formula (I), R¹⁰, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹⁰ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹⁰ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (I), R¹⁰, at each occurrence, is independently C₆-C₁₀ membered aryl; wherein each R¹⁰ C₆-C₁₀ membered aryl is optionally substituted with one or more C₁-C₆ alkoxy.

In one embodiment of Formula (I), R¹¹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹ C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I. In another embodiment of Formula (I), R¹¹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹¹ C₆-C₁₀ membered aryl, is optionally substituted with one or more C₁-C₆ alkoxy.

In one embodiment of Formula (I), R¹², at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹² C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹² C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I. In another embodiment of Formula (I), R¹², at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² C₁-C₆ alkyl is optionally substituted with one or more F; wherein each 4-12 membered heterocyclyl is optionally substituted with one or more C₁-C₆ alkyl.

In one embodiment of Formula (I), R¹³, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In another R¹³, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, and 4-12 membered heterocyclyl; wherein each R¹³ C₆-C₁₀ membered aryl and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, and Cl.

In one embodiment of Formula (I), R¹⁴, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (I), R¹⁴, at each occurrence, is independently C₁-C₆ alkyl; wherein each R¹⁴ C₁-C₆ alkyl is optionally substituted with one or more independently selected 4-12 membered heterocyclyl.

One embodiment pertains to compounds of Formula (I), or a pharmaceutically acceptable salt thereof,

wherein

-   -   A¹ is selected from the group consisting of

-   -   X¹ is C(R^(2A));     -   X² is N or C(R^(2B));     -   X³ is C(R^(2C));     -   X⁴ is N or C(R^(2D));     -   R¹ is selected from the group consisting of hydrogen, CN, and         C₁-C₆ alkyl; wherein the R¹ C₁-C₆ alkyl is optionally         substituted with one or more substituents independently selected         from the group consisting of R⁷, OR⁷, N(R⁷)₂, C(O)OH, OH, and         CN;     -   one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the         remaining are independently selected from the group consisting         of hydrogen, R⁸, OR⁸, C(O)OR⁸, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH,         CN, F, Cl, and Br; or     -   two of R^(2A), R^(2B), R^(2C), and R^(2D) on adjacent carbons         form a 4-7 membered heterocyclyl; and the remaining are         hydrogen;     -   R³ is selected from the group consisting of C₁-C₆ alkyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and         4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkoxy         and phenyl; wherein the R³ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl and 4-12 membered heterocyclyl are         optionally substituted with one or more substituents         independently selected from the group consisting of R⁹, OR⁹,         C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹,         N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br; R⁴ is selected         from the group consisting of hydrogen and C₁-C₆ alkyl; wherein         the R⁴ C₁-C₆ alkyl is optionally substituted with one or more         R¹⁰;     -   R^(5A), R^(5B), R^(5C), and R^(5D) are each independently         selected from the group consisting of hydrogen and C₁-C₆ alkyl;     -   R^(6A), R^(6B), R^(6C), and R^(6D) are each independently         hydrogen;     -   R⁷, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl;         wherein each R⁷ C₁-C₆ alkyl is optionally substituted with one         or more C₁-C₆ alkoxy; wherein each R⁷ 5-11 membered heteroaryl         and 4-12 membered heterocyclyl is optionally substituted with         one or more substituents independently selected from the group         consisting of C₁-C₆ alkoxy, C₁-C₆ haloalkyl, F, and Cl;     -   R⁸, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered         heterocyclyl; wherein each R⁸ C₁-C₆ alkyl and C₂-C₆ alkenyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹¹, OR¹¹,         C(O)OR¹¹, OH, and F; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11         membered heteroaryl and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of R¹², OR¹², N(R¹²)₂ and F;     -   R⁹, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁         cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹         C₁-C₆ alkyl is optionally substituted with one or more         substituents independently selected from the group consisting of         R¹³, OR¹³, C(O)R¹³, N(R¹³)₂, OH, F, and Cl; wherein each R⁹6-10         membered aryl and 4-12 membered heterocyclyl are optionally         substituted with one or more substituents independently selected         from the group consisting of R¹⁴, oxo, and F;     -   R¹⁰, at each occurrence, is independently C₆-C₁₀ membered aryl;         wherein each R¹⁰ C₆-C₁₀ membered aryl is optionally substituted         with one or more C₁-C₆ alkoxy;     -   R¹¹, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁         cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹¹         C₆-C₁₀ membered aryl is optionally substituted with one or more         C₁-C₆ alkoxy;     -   R¹², at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁         cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹²         C₁-C₆ alkyl is optionally substituted with one or more F;         wherein each 4-12 membered heterocyclyl is optionally         substituted with one or more C₁-C₆ alkyl;     -   R¹³, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl and 4-12         membered heterocyclyl; wherein each R¹³ C₆-C₁₀ membered aryl and         4-12 membered heterocyclyl is optionally substituted with one or         more substituents independently selected from the group         consisting of C₁-C₆ alkyl and Cl; and     -   R¹⁴, at each occurrence, is independently C₁-C₆ alkyl; wherein         each R¹⁴ C₁-C₆ alkyl is optionally substituted with one or more         4-12 membered heterocyclyl;     -   with the proviso that R³ is not methyl;     -   with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D)         are each hydrogen, R¹ is not hydrogen;     -   with the proviso that, when R³ is naphthyl, R^(2C) is not         4-(1-methylethyl)phenoxy; and     -   with the proviso that, when R¹ is C₁-alkyl, R³ is not         3-pyridinyl or 4-cyanobenzyl.

One embodiment pertains to a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

-   4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1R)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   1-benzyl-4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   1-benzyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   1-ethyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1R)-8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1S)-8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-N-(2,2-difluoro-2H-1,3-benzodioxole-4-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-1-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (6S)-6-methyl-N-(naphthalene-1-sulfonyl)-7,8-dihydro-2H,6H-indeno[4,5-d][1,3]dioxole-6-carboxamide; -   (6R)-6-methyl-N-(naphthalene-1-sulfonyl)-7,8-dihydro-2H,6H-indeno[4,5-d][1,3]dioxole-6-carboxamide; -   (1S)-6-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-6-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(naphthalene-1-sulfonyl)-6,7,8,9-tetrahydro-2H-naphtho[1,2-d][1,3]dioxole-6-carboxamide; -   (1S)-7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-1-ethyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-(cyclopropylmethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   1-butyl-4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(8-hydroxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   8-bromo-5-ethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-N-(naphthalene-1-sulfonyl)-1-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-[(6-chloropyridin-3-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-[(6-methoxypyridin-2-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(5-chloronaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   8-bromo-N-(naphthalene-1-sulfonyl)-5-[(propan-2-yl)oxy]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-bromo-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-1-ethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(1-benzothiophene-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   8-bromo-5-(2-methoxyethoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1S)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1R)-8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1S)-4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-7-ethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-N-(naphthalene-1-sulfonyl)-7-[(propan-2-yl)oxy]-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-7-(cyclopropylmethoxy)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   8-bromo-5-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-methoxy-8-(4-methylphenyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-bromo-7-(difluoromethoxy)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1R)-8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1S)-5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1R)-5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1S)-8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1R)-8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-1-ethyl-N-(1-methyl-1H-indole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   5-methoxy-8-(2-methylpropyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-methoxy-5-(2-methylpropyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-cyclobutyl-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-chloro-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1S)-4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   5,8-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-1-ethyl-N-(1-methyl-1H-indole-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   7-methoxy-4-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-N-(imidazo[1,2-a]pyridine-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   2-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   (1S)-4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   8-cyclobutyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   7-cyclobutyl-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   5-cyclopropyl-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1S)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-7-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-7-methoxy-N-(2-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   (1R)-4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-N-(5-hydroxynaphthalene-1-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   (7S)-2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   (7R)-2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   (1R)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide; -   4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide; -   4-chloro-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide; -   4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide; -   2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   (8S)-4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide; -   (8R)-4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide; -   (1S)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (8R)-4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide; -   (8S)-4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide; -   (1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   7-methoxy-N-(naphthalene-1-sulfonyl)-4-(prop-1-en-2-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-(2-hydroxypropan-2-yl)-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   2-cyclobutyl-5-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   2-cyclobutyl-5-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   7-methoxy-N-(naphthalene-1-sulfonyl)-4-(oxolan-2-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   7-methoxy-4-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   7-methoxy-4-(2-methylpropyl)-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (7S)-2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   (7R)-2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   (7S)-2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   (7R)-2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   (7S)-2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   (7R)-2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   7-methoxy-3,3-dimethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (7R)-2-cyclobutyl-5-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   N-(benzenesulfonyl)-4-chloro-1-methyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-6-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)-6-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2-chlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-methoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5,6-dimethoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-chloro-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   6-fluoro-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1R)-5-methoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1S)—N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   6,7-dimethoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-2-carboxamide; -   (1R)—N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1S)-6-methoxy-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   7-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4,5-difluoro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   1,5-dimethyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-ethylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2-ethylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(3-chlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(4-chlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2-fluorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-4-chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(2-nitrobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-(3,6-dihydro-2H-pyran-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-cyclobutyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-phenyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-[2-(trifluoromethyl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-bromobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-[(propan-2-yl)oxy]-2,3-dihydro-1H-indene-1-carboxamide; -   7-bromo-4-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-(2-methoxypyridin-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   5-methoxy-N-(quinoline-8-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   (1R)-5-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-5-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1S)-4-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(naphthalene-1-sulfonyl)-1-[(pyrrolidin-1-yl)methyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-2-carboxamide; -   1-methyl-N-(naphthalene-1-sulfonyl)-6-(trifluoromethoxy)-2,3-dihydro-1H-indene-1-carboxamide; -   8-bromo-5-hydroxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5,6-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-amide; -   N-(naphthalene-1-sulfonyl)-2,3,7,8,9,10-hexahydronaphtho[1,2-b][1,4]dioxine-7-carboxamide; -   6,7-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-N-(2-chlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(2-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-[5-methyl-2-(propan-2-yl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-[3-chloro-2-(methoxymethyl)benzene-1-sulfonyl]-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(2-fluorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(2-phenoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-[2-(trifluoromethoxy)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-[2-(difluoromethoxy)benzene-1-sulfonyl]-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2,5-dimethylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-[2-(2-methoxyethoxy)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   N-([1,1′-biphenyl]-2-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(benzenesulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2,1,3-benzothiadiazole-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(naphthalene-1-sulfonyl)-1-[(oxolan-3-yl)methyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(naphthalene-1-sulfonyl)-1-[2-(1H-pyrazol-1-yl)ethyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-[(5-methoxypyridin-2-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-[(2-methoxypyridin-4-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(naphthalene-1-sulfonyl)-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2,3-dihydro-1,4-benzodioxine-5-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-bromonaphthalene-1-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(4-fluoronaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(5-bromonaphthalene-1-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(5,6,7,8-tetrahydronaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(3,4-dihydroquinoline-1(2H)-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-(hydroxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-cyclobutyl-N-(4-cyclobutylnaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-cyclobutyl-N-(5-cyclobutylnaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   8-bromo-5-(cyclohexylmethoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-bromo-5-[(3-methoxyphenyl)methoxy]-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-bromo-5-[(3-methoxyphenyl)methoxy]-N-[(3-methoxyphenyl)methyl]-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide;     ethyl({4-bromo-5-[(naphthalene-1-sulfonyl)carbamoyl]-5,6,7,8-tetrahydronaphthalen-1-yl}oxy)acetate; -   8-bromo-5-(cyclopentyloxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-(benzyloxy)-8-bromo-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   N-benzyl-5-(benzyloxy)-8-bromo-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-bromo-N-(naphthalene-1-sulfonyl)-5-[(oxetan-3-yl)oxy]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-bromo-N-(naphthalene-1-sulfonyl)-5-[(oxan-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-bromo-5-(2-hydroxy-2-methylpropoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   6,8-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-methoxy-N-(naphthalene-1-sulfonyl)-8-[4-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-methoxy-N-(naphthalene-1-sulfonyl)-8-[(E)-2-phenylethenyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-(2,2-difluoro-2H-1,3-benzodioxol-4-yl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-(2-fluoro-4-methylphenyl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-methoxy-N-(naphthalene-1-sulfonyl)-8-(2-phenoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   N-(3-bromo-2-methylbenzene-1-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(3-fluoro-2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-[2-(methoxymethyl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2,3-difluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-[2-(2,2-difluoroethoxy)benzene-1-sulfonyl]-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(quinoxaline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(3-chloro-2-fluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2,3-dichlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(1-methyl-1H-indole-3-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   5-[2-(1,3-dioxan-2-yl)ethyl]-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-cyano-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   5-cyano-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-N-(3-cyclobutyl-2-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(isoquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carb     oxamide; -   8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-bromo-7-methoxy-N-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-N-(8-fluoroquinoline-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   7-ethyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carb     oxamide; -   8-methoxy-N-(naphthalene-1-sulfonyl)-5-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-methoxy-N-(naphthalene-1-sulfonyl)-5-[(E)-2-phenylethenyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-methoxy-8-(6-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-bromo-N-(2-ethoxyquinoline-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   8-methoxy-N-(naphthalene-1-sulfonyl)-5-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-1-ethyl-N-[2-methyl-3-(piperidin-1-yl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-[3-(3,3-difluoroazetidin-1-yl)-2-methylbenzene-1-sulfonyl]-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-[3-(3,3-difluoropyrrolidin-1-yl)-2-methylbenzene-1-sulfonyl]-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   5-chloro-8-hydroxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-methoxy-N-(naphthalene-1-sulfonyl)-8-[6-(trifluoromethyl)pyridin-3-yl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-(3,6-dihydro-2H-pyran-4-yl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-(6-cyclopropylpyridin-3-yl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-bromo-7-methoxy-N-[2-(propan-2-yl)quinoline-5-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-7-methoxy-N-(5-methoxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   methyl     7-methoxy-1-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-indene-4-carboxylate; -   methyl     5-[(4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]naphthalene-1-carboxylate; -   5-chloro-8-[2-(morpholin-4-yl)ethoxy]-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-1-methyl-N-(phenylmethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2-methoxyethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(propane-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   8-methoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide; -   5-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide; -   4-methoxy-N-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(2-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(5-methylpyridine-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(oxane-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(3-methoxypropane-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(2-methoxyethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(propane-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(5-methylpyridine-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-hydroxybenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(phenylmethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(6-hydroxynaphthalene-2-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(4-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(5-acetamido-1,3,4-thiadiazole-2-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-[5-methyl-2-(propan-2-yl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   N-[4-(methanesulfonyl)benzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(3-nitrobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-chloro-3-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(6-chloro-1,1-dioxo-1,2-dihydro-1λ⁶,2,4-benzothiadiazine-7-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(2-methyl-5-nitrobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-acetamido-2-methylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-chloro-2-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(3-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-[4-(3-oxobutanamido)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2,4-dichlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-amino-2-chloro-5-methylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-chloro-5-methylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-chloro-5-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-acetamidobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-acetamido-2-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-butanamidobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2,4-dihydroxy-6-methylpyrimidine-5-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-cyanobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(2-oxo-2H-1-benzopyran-6-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   ethyl     4-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]benzoate; -   N-(2,4-dimethyl-3-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-{2-chloro-5-[(2,6-dimethylphenyl)carbamoyl]-4-hydroxybenzene-1-sulfonyl}-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-[1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-[3-({[2S)-1-ethylpyrrolidin-2-yl]methyl}carbamoyl)-4-methoxybenzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(6-ethoxy-1,3-benzothiazole-2-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-hexanoylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-[4-(4-{2-[(1S)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazin-1-yl)benzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   propan-2-yl     2-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]benzoate; -   N-{4-[(3-hydroxy-3-methylbutyl)amino]-3-nitrobenzene-1-sulfonyl}-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-[2-chloro-5-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)benzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-{7[(4-chlorophenyl)methyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonyl}-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(9-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purine-8-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-{4-[(dimethylamino)methyl]benzene-1-sulfonyl}-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-cyano-3-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-hydroxy-3-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(3-cyanobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(5-bromopyridine-3-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(6-hydroxypyridine-3-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(4-cyano-1,3-dimethyl-1H-pyrazole-5-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   tert-butyl     5-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-1,3-dimethyl-1H-pyrazole-4-carboxylate; -   N-[4-(hydroxymethyl)-1,3-dimethyl-1H-pyrazole-5-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(3-chloro-2-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2,6-difluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4,5-dimethoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(5-chloro-2-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2,5-difluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-chloro-5-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2,6-dichlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2,4-difluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-[1-(2-methoxyethyl)-1H-pyrazole-4-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   N-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2,4-dimethyl-1,3-thiazole-5-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(pyridine-3-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   2-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-N,N-dimethylpyridine-3-carboxamide; -   N-(2-cyanopyridine-3-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-methoxy-N-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-(6-methoxypyridin-3-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-[6-(piperidin-1-yl)pyridin-3-yl]-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(2-methylpyridin-3-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-(6-fluoropyridin-3-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4[6-(dimethylamino)pyridin-3-yl]-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-(5-fluoropyridin-3-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(5-methylpyridin-3-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-(2-fluoropyridin-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-(3-fluoropyridin-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(3-methylpyridin-4-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(2-methylpyridin-4-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(1H-pyrazol-4-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(1H-pyrazol-5-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(thiophen-3-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(3-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(5-methylfuran-2-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(2-methylfuran-3-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)-4-(1-methyl-1H-pyrazol-5-yl)-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)—N-(2-aminopyridine-3-sulfonyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   N-(6-aminopyridine-2-sulfonyl)-1,5-dimethyl-2,3-dihydro-1H-indene-1-carboxamide; -   (1R)—N-(6-aminopyridine-2-sulfonyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   N-(6-aminopyridine-2-sulfonyl)-8-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-N-(naphthalene-1-sulfonyl)-1-[2-(pyrrolidin-1-yl)ethyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2,4-dichlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2,4-dimethylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2,6-difluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2,5-dichlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(3-chlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2-chloro-5-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2-cyanobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2,6-dimethoxybenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-[2-(trifluoromethyl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2-chloro-6-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(4-chlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-[2-methyl-6-(trifluoromethyl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2-cyano-3-fluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(1-methylcyclopropane-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-([1,1′-biphenyl]-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-{4-[(dimethylamino)methyl]benzene-1-sulfonyl}-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(2-chloropyridine-3-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(quinoline-6-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   2-[(4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-N,N-dimethylpyridine-3-carboxamide; -   4-chloro-N-(cyclohexanesulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-{4-[4-(propan-2-yl)piperazin-1-yl]pyridine-3-sulfonyl}-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-{2-[2-(piperidin-1-yl)ethoxy]benzene-1-sulfonyl}-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(4-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(phenylmethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindole-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(4-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(4-phenoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(3-cyanobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-(1H-pyrazole-3-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   3-{4-chloro-1-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-inden-1-yl}propanoic     acid; -   4-chloro-N-(naphthalene-1-sulfonyl)-1-[(pyridin-2-yl)methyl]-2,3-dihydro-1H-indene-1-carboxamide; -   5-methoxy-N-(naphthalene-1-sulfonyl)-8-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   methyl     2-chloro-6-[(4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]benzoate; -   4-chloro-1-ethyl-N-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-7-hydroxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   5-methoxy-8-(morpholin-4-yl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-methoxy-N-(naphthalene-1-sulfonyl)-8-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-1-(cyanomethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-N-(3-chloro-2-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; -   8-chloro-1-cyano-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-bromo-7-methoxy-N-(2-methoxypyridine-3-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   N-(2-aminopyridine-3-sulfonyl)-4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   N-(6-aminopyridine-2-sulfonyl)-4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-N-(4-ethoxynaphthalene-1-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-7-methoxy-N-(4-methoxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-bromo-7-methoxy-N-([1,2,4]triazolo[4,3-a]pyridine-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   8-methoxy-N-(naphthalene-1-sulfonyl)-5-(pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   5-(6-cyclopropylpyridin-3-yl)-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-methoxy-N-(naphthalene-1-sulfonyl)-5-(pyridin-4-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-methoxy-5-(6-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   7-methoxy-4-(pyrimidin-5-yl)-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   4-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   8-methoxy-5-(4-methylphenyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   8-methoxy-N-(naphthalene-1-sulfonyl)-5-[6-(trifluoromethyl)pyridin-3-yl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   4-chloro-1-ethyl-N-[2-methyl-3-(morpholin-4-yl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; -   4-chloro-1-ethyl-N-{3-[(2-methoxyethyl)(methyl)amino]-2-methylbenzene-1-sulfonyl}-2,3-dihydro-1H-indene-1-carboxamide; -   5-methoxy-N-(naphthalene-1-sulfonyl)-8-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; -   2,3-dimethoxy-N-(2-methylbenzene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   N-(2-methylbenzene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   2,3-dimethoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; -   2-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide; -   2-chloro-6-[(4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]benzoic     acid; -   1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide; -   5-[(4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]naphthalene-1-carboxylic     acid; -   7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   7-methoxy-1-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-indene-4-carboxylic     acid; -   methyl     7-methoxy-3-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-indene-4-carboxylate; -   4-(hydroxymethyl)-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; -   7-methoxy-N⁴-methyl-N¹-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1,4-dicarboxamide; -   7-methoxy-N⁴,N⁴-dimethyl-N¹-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1,4-dicarboxamide;     and -   7-methoxy-N-(naphthalene-1-sulfonyl)-4-[(pyrrolidin-1-yl)methyl]-2,3-dihydro-1H-indene-1-carboxamide.

One embodiment pertains to (1S)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; or a pharmaceutically acceptable salt thereof. Another embodiment pertains to (1R)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; or a pharmaceutically acceptable salt thereof. Another embodiment pertains to (1S)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; or a pharmaceutically acceptable salt thereof. Another embodiment pertains to (1R)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; or a pharmaceutically acceptable salt thereof. Another embodiment pertains to (1S)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; or a pharmaceutically acceptable salt thereof. Another embodiment pertains to (1R)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; or a pharmaceutically acceptable salt thereof.

One embodiment pertains to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Examples: I-1; I-2; I-3; I-4; I-5; I-6; I-7; I-8; I-9; I-10; I-11; I-12; I-13; I-14; I-15; I-16; I-17; I-18; I-19; I-20; I-21; I-22; I-23; I-24; I-26; I-27; I-28; I-29; I-30; I-31; I-32; I-33; I-34; I-35; I-36; I-37; I-38; I-39; I-40; I-41; I-42; I-43; I-44; I-45; I-46; I-47; I-48; I-49; I-50; I-51; I-52; I-53; I-54; I-55; I-56; I-57; I-58; I-59; I-60; I-61; I-62; I-63; I-64; I-65; I-66; I-67; I-68; I-69; I-70; I-71; I-72; I-73; I-74; I-75; I-76; I-77; I-78; I-79; I-80; I-81; I-82; I-83; I-84; I-85; I-86; I-87; I-88; I-89; I-90; I-91; I-92; I-93; I-94; I-95; I-96; I-97; I-98; I-99; I-100; I-101; I-102; I-103; I-104; I-105; I-106; I-107; I-108; I-109; I-110; I-111; I-112; I-113; I-114; I-115; I-116; I-117; I-118; I-119; I-120; I-121; I-122; I-123; I-124; I-125; I-126; I-127; I-128; I-129; I-130; I-131; I-132; I-133; I-134; I-135; I-136; I-137; I-138; I-139; I-140; I-141; I-142; I-143; I-144; I-145; I-146; I-147; I-148; I-149; I-151; I-152; I-153; I-154; I-155; II-1; II-2; II-3; II-4; II-5; II-6; II-8; II-9; II-10; II-12; II-13; II-15; II-16; II-18; II-19; II-20; II-21; II-22; II-23; II-24; II-25; II-26; II-27; II-28; II-29; II-30; II-31; II-32; II-33; II-34; II-35; II-36; II-37; II-38; II-39; II-40; II-41; II-42; II-43; II-44; II-45; II-46; II-47; II-48; II-49; II-50; II-52; II-53; II-54; II-55; II-56; II-57; II-58; II-59; II-60; II-61; II-62; II-63; II-64; II-65; II-66; II-67; II-69; II-70; II-71; II-72; II-73; II-74; II-75; II-76; II-77; II-78; II-79; II-80; II-81; II-82; II-83; II-84; II-85; II-86; II-87; II-88; II-89; II-90; II-91; II-92; II-93; II-94; II-95; II-96; II-97; II-98; II-99; II-100; II-101; II-102; II-103; II-104; II-105; II-106; II-107; II-108; II-109; II-110; II-111; II-112; II-113; II-114; II-115; II-116; II-117; II-118; II-119; II-120; II-121; II-122; II-123; II-124; II-125; II-126; II-127; II-128; II-129; II-130; II-131; II-132; II-133; II-134; II-135; II-136; III-3; III-4; III-5; III-6; III-7; III-9; III-11; III-12; III-13; III-14; III-15; III-16; III-17; III-18; III-19; III-20; III-21; III-22; III-23; III-24; III-25; III-26; III-27; III-28; III-29; III-30; III-31; III-32; III-33; III-34; III-35; III-36; III-37; III-38; III-39; III-40; III-41; III-42; III-43; III-44; III-45; III-46; III-47; III-48; III-49; III-50; III-51; III-52; III-53; III-54; III-55; III-56; III-57; III-58; III-59; III-60; III-61; III-62; III-63; III-64; III-65; III-66; III-67; III-68; III-69; III-70; III-71; III-72; III-73; III-74; III-75; III-76; III-77; III-78; III-79; III-80; III-81; III-82; III-83; III-84; III-85; III-86; III-87; III-88; III-89; III-90; III-91; III-92; III-93; III-94; III-95; III-96; III-97; III-98; III-99; III-100; III-101; III-102; III-103; III-104; III-105; III-106; III-107; III-108; III-109; III-110; III-111; III-112; III-113; III-114; III-115; III-116; III-117; III-118; III-119; III-120; III-121; III-122; III-123; III-124; III-125; III-126; III-127; III-128; III-129; III-130; III-131; III-132; III-133; III-134; III-135; III-136; III-137; III-138; III-139; III-140; III-141; III-142; III-143; III-144; III-145; III-146; III-147; III-148; III-149; III-150; III-151; III-152; III-153; III-154; III-155; III-156; III-157; III-158; III-159; III-160; III-161; III-162; III-163; III-164; III-165; III-166; III-167; III-168; III-169; III-170; III-171; III-172; III-173; III-174; III-175; III-177; III-178; III-179; III-180; III-181; III-182; III-183; III-184; III-185; III-186; III-187; and III-188.

Formula (II)

One embodiment pertains to compounds of Formula (II), or a pharmaceutically acceptable salt thereof,

wherein

-   -   R¹ is selected from the group consisting of hydrogen, OH, CN,         C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the         R¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy         are optionally substituted with one or more substituents         independently selected from the group consisting of R⁷, OR⁷,         SR⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I;         wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl,         C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered         heterocyclyl are optionally substituted with one or more         substituents independently selected from the group consisting of         C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,         C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the         remaining are independently selected from the group consisting         of hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,         C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; or     -   two of R^(2A), R^(2B), R^(2C), and R^(2D) on adjacent carbons         form a fused ring selected from the group consisting of phenyl,         5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl,         and 4-7 membered heterocyclyl; and the remaining are         independently selected from the group consisting of hydrogen,         R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,         C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein the phenyl, 5-6 membered heteroaryl, C₃-C₇         cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of R⁸, OR⁸,         C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH,         CN, NO₂, F, Cl, Br and I;     -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆         alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆         alkenyl, and C₂-C₆ alkynyl are optionally substituted with one         or more substituents independently selected from the group         consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br         and I; wherein the R³ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl are optionally substituted with one or         more substituents independently selected from the group         consisting of R⁹, OR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂,         C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH,         oxo, CN, NO₂, F, Cl, Br and I;     -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆         alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with         one or more substituents independently selected from the group         consisting of R¹⁰, OR¹⁰, SR¹⁰, NHR¹⁰, N(R¹⁰)₂, NH₂, C(O)OH, OH,         oxo, CN, NO₂, F, Cl, Br and I;     -   R^(5A), R^(5B), R^(5C), and R^(5D) are each independently         selected from the group consisting of hydrogen, C₁-C₆ alkyl,         C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl; wherein the         R^(5A), R^(5B), R^(5C), and R^(5D) C₁-C₆ alkyl, C₂-C₆ alkenyl,         C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with         one or more substituents independently selected from the group         consisting of 6-10 membered aryl, 5-11 membered heteroaryl,         C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered         heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and         I; wherein the R^(5A), R^(5B), R^(5C), and R^(5D) 6-10 membered         aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl are optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo,         CN, NO₂, F, Cl, Br and I; or     -   R^(5A) and R^(5B), together with the carbon atom to which they         are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7         membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic         cycloalkyl and the 4-7 membered monocyclic heterocycle are each         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R^(5C) and R^(5D) are each independently selected from the group         consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆         alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R^(5C) and R^(5D) C₁-C₆         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are         optionally substituted with one or more substituents         independently selected from the group consisting of 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆         thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5C)         and R^(5D) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; or     -   R^(5A) and R^(5B) are each independently selected from the group         consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆         alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R^(5A) and R^(5B) C₁-C₆         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are         optionally substituted with one or more substituents         independently selected from the group consisting of 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆         thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5A)         and R^(5B) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R^(5C) and R^(5D), together with the carbon atom to which they         are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7         membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic         cycloalkyl and the 4-7 membered monocyclic heterocycle are each         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R^(6A) and R^(6B) are each independently hydrogen;     -   R⁷, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆         alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁷ 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and         I;     -   R⁸, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹¹, OR¹¹,         C(O)OR¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl is optionally substituted with one or more         substituents independently selected from the group consisting of         R¹², OR¹², C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, oxo, CN,         NO₂, F, Cl, Br and I;     -   R⁹, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹³, OR¹³,         SR¹³, C(O)R¹³, NHR¹³, N(R¹³)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein each R⁹ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl are optionally substituted with one or         more substituents independently selected from the group         consisting of R¹⁴, OR¹⁴, C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴, SO₂R¹⁴,         NHR¹⁴, N(R¹⁴)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R¹⁰, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹⁰ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of OH, oxo, CN,         NO₂, F, Cl, Br and I; wherein each R¹⁰ C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6         membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I;

R¹¹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹ C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I;

-   -   R¹², at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered         aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁         cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹²         C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one         or more substituents independently selected from the group         consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each         R¹² C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered         heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, F, Cl, Br and I;     -   R¹³, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of OH, oxo, CN,         NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6         membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R¹⁴, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered         heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   with the proviso that R³ is not methyl;     -   with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D)         are each hydrogen, R¹ is not hydrogen;     -   with the proviso that, when R³ is naphthyl, R^(2C) is not         4-(1-methylethyl)phenoxy; and     -   with the proviso that, when R¹ is C₁-alkyl, R³ is not         3-pyridinyl or 4-cyanobenzyl.

In one embodiment of Formula (II), R¹ is selected from the group consisting of hydrogen, OH, CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, SR⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (II), R¹ is selected from the group consisting of hydrogen, CN, and C₁-C₆ alkyl; wherein the R¹ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, N(R⁷)₂, C(O)OH, OH, and CN. In another embodiment of Formula (II), R¹ is hydrogen. In another embodiment of Formula (II), R¹ is CN. In another embodiment of Formula (II), R¹ is C₁-C₆ alkyl; which is unsubstituted. In another embodiment of Formula (II), R¹ is C₁-C₆ alkyl; wherein the R¹ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, N(R⁷)₂, C(O)OH, OH, and CN.

In one embodiment of Formula (II), one of R^(2A), R^(2B), R^(2C) and R^(2D) is hydrogen, and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D) a are each hydrogen, R¹ is not hydrogen. In another embodiment of Formula (II), one of R^(2A), R^(2B), R^(2C), and R^(2D) a is hydrogen, and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, F, Cl, and Br; with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D) are each hydrogen, R¹ is not hydrogen. In another embodiment of Formula (II), R^(2A), R^(2B), R^(2C), and R^(2D) a are hydrogen; with the proviso that, R¹ is not hydrogen.

In one embodiment of Formula (II), two of R^(2A), R^(2B), R^(2C), and R^(2D) on adjacent carbons form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein the phenyl, 5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (II), R^(2C) and R^(2D) form a 4-7 membered heterocyclyl; and R^(2A) and R^(2B) are independently hydrogen.

In one embodiment of Formula (II), R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (II), R³ is selected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy and phenyl; wherein the R³ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (II), R³ is C₁-C₆ alkyl; wherein the R³ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy and phenyl. In another embodiment of Formula (II), R³ is 6-10 membered aryl; wherein the R³ 6-10 membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (II), R³ is 5-11 membered heteroaryl; wherein the R³ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (II), R³ is C₃-C₁₁ cycloalkyl; wherein the R³ C₃-C₁₁ cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (II), R³ is 4-12 membered heterocyclyl; wherein the R³ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br.

In one embodiment of Formula (II), R⁴ is selected from the group consisting of hydrogen and C₁-C₆ alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹⁰, OR¹⁰, SR¹⁰, NHR¹⁰, N(R¹⁰)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (II), R⁴ is hydrogen. In another embodiment of Formula (II), R⁴ is C₁-C₆ alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with one or more R¹⁰.

In one embodiment of Formula (II), R^(5A), R^(5B), R^(5C), and R^(5D) are each independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R^(5A), R^(5B), R^(5C), and R^(5D) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5A), R^(5B), R^(5C), and R^(5D) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; or R^(5A) and R^(5B), together with the carbon atom to which they are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic cycloalkyl and the 4-7 membered monocyclic heterocycle are each optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and R^(5C) and R^(5D) are each independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R^(5C) and R^(5D) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5C) and R^(5D) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; or R^(5A) and R^(5B) are each independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R^(5A) and R^(5B) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5A) and R^(5B) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and R^(5C) and R^(5D), together with the carbon atom to which they are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic cycloalkyl and the 4-7 membered monocyclic heterocycle are each optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (II), R^(5A), R^(5B), R^(5C), and R^(5D) are each independently hydrogen. In another embodiment of Formula (II), R^(5A), R^(5B), R^(5C), and R^(5D) are each independently C₁-C₆ alkyl.

In one embodiment of Formula (II), R^(6A) and R^(6B) are each independently hydrogen.

In one embodiment of Formula (II), R⁷, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁷ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (II), R⁷, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁷ C₁-C₆ alkyl is optionally substituted with one or more C₁-C₆ alkoxy; wherein each R⁷ 5-11 membered heteroaryl and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆ haloalkyl, F, and Cl.

In one embodiment of Formula (II), R⁸, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹¹, OR¹¹, C(O)OR¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹², OR¹², C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (II), R⁸, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁸ C₁-C₆ alkyl and C₂-C₆ alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹¹, OR¹¹, C(O)OR¹¹, OH, and F; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹², OR¹², N(R¹²)₂, and F.

In one embodiment of Formula (II), R⁹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹³, OR¹³, SR¹³, C(O)R¹³, NHR¹³, N(R¹³)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴, OR¹⁴, C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴, SO₂R¹⁴, NHR¹⁴, N(R¹⁴)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (II), R⁹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹³, OR¹³, C(O)R¹³, N(R¹³)₂, OH, F, and Cl; wherein each R⁹ 6-10 membered aryl and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴, oxo, and F.

In one embodiment of Formula (II), R¹⁰, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹⁰ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹⁰ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (II), R¹⁰, at each occurrence, is independently C₆-C₁₀ membered aryl; wherein each R¹⁰ C₆-C₁₀ membered aryl is optionally substituted with one or more C₁-C₆ alkoxy.

In one embodiment of Formula (II), R¹¹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹ C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I. In another embodiment of Formula (II), R¹¹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹¹ C₆-C₁₀ membered aryl is optionally substituted with one or more C₁-C₆ alkoxy.

In one embodiment of Formula (II), R¹², at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹² C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹² C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I. In another embodiment of Formula (II), R¹², at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² C₁-C₆ alkyl is optionally substituted with one or more F; wherein each 4-12 membered heterocyclyl is optionally substituted with one or more C₁-C₆ alkyl.

In one embodiment of Formula (II), R¹³, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In another R¹³, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, and 4-12 membered heterocyclyl; wherein each R¹³ C₆-C₁₀ membered aryl and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, and Cl.

In one embodiment of Formula (II), R¹⁴, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (II), R¹⁴, at each occurrence, is independently C₁-C₆ alkyl; wherein each R¹⁴ C₁-C₆ alkyl is optionally substituted with one or more independently selected 4-12 membered heterocyclyl.

One embodiment pertains to compounds of Formula (II), or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is selected from the group consisting of hydrogen, CN, and         C₁-C₆ alkyl; wherein the R¹ C₁-C₆ alkyl is optionally         substituted with one or more substituents independently selected         from the group consisting of R⁷, OR⁷, N(R⁷)₂, C(O)OH, OH, and         CN;     -   one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the         remaining are independently selected from the group consisting         of hydrogen, R⁸, OR⁸, C(O)OR⁸, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH,         CN, F, Cl, and Br; or     -   two of R^(2A), R^(2B), R^(2C), and R^(2D) on adjacent carbons         form a 4-7 membered heterocyclyl; and the remaining are         hydrogen;     -   R³ is selected from the group consisting of C₁-C₆ alkyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and         4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkoxy         and phenyl; wherein the R³ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl and 4-12 membered heterocyclyl are         optionally substituted with one or more substituents         independently selected from the group consisting of R⁹, OR⁹,         C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹,         N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br;     -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆         alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with         one or more R¹⁰;     -   R^(5A), R^(5B), R^(5C), and R^(5D) are each independently         selected from the group consisting of hydrogen and C₁-C₆ alkyl;     -   R^(6A), R^(6B), R^(6C), and R^(6D) are each independently         hydrogen;     -   R⁷, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl;         wherein each R⁷ C₁-C₆ alkyl is optionally substituted with one         or more C₁-C₆ alkoxy; wherein each R⁷ 5-11 membered heteroaryl         and 4-12 membered heterocyclyl is optionally substituted with         one or more substituents independently selected from the group         consisting of C₁-C₆ alkoxy, C₁-C₆ haloalkyl, F, and Cl;     -   R⁸, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered         heterocyclyl; wherein each R⁸ C₁-C₆ alkyl and C₂-C₆ alkenyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹¹, OR¹¹,         C(O)OR¹¹, OH, and F; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11         membered heteroaryl and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of R¹², OR¹², N(R¹²)₂ and F;     -   R⁹, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁         cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹         C₁-C₆ alkyl is optionally substituted with one or more         substituents independently selected from the group consisting of         R¹³, OR¹³, C(O)R¹³, N(R¹³)₂, OH, F, and Cl; wherein each R⁹ 6-10         membered aryl and 4-12 membered heterocyclyl are optionally         substituted with one or more substituents independently selected         from the group consisting of R¹⁴, oxo, and F;     -   R¹⁰, at each occurrence, is independently C₆-C₁₀ membered aryl;         wherein each R¹⁰ C₆-C₁₀ membered aryl is optionally substituted         with one or more C₁-C₆ alkoxy;     -   R¹¹, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁         cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹¹         C₆-C₁₀ membered aryl is optionally substituted with one or more         C₁-C₆ alkoxy;     -   R¹², at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁         cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹²         C₁-C₆ alkyl is optionally substituted with one or more F;         wherein each 4-12 membered heterocyclyl is optionally         substituted with one or more C₁-C₆ alkyl;     -   R¹³, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl and 4-12         membered heterocyclyl; wherein each R¹³ C₆-C₁₀ membered aryl and         4-12 membered heterocyclyl is optionally substituted with one or         more substituents independently selected from the group         consisting of C₁-C₆ alkyl and Cl; and     -   R¹⁴, at each occurrence, is independently C₁-C₆ alkyl; wherein         each R¹⁴ C₁-C₆ alkyl is optionally substituted with one or more         4-12 membered heterocyclyl;     -   with the proviso that R³ is not methyl;     -   with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D)         are each hydrogen, R¹ is not hydrogen;     -   with the proviso that, when R³ is naphthyl, R^(2C) is not         4-(1-methylethyl)phenoxy; and     -   with the proviso that, when R¹ is C₁-alkyl, R³ is not         3-pyridinyl or 4-cyanobenzyl.

One embodiment pertains to a compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Examples: I-2; I-3; I-4; I-9; I-10; I-11; I-12; I-15; I-24; I-32; I-33; I-34; I-40; I-41; I-45; I-48; I-49; I-50; I-56; I-57; I-60; I-61; I-62; I-63; I-64; I-65; I-67; I-68; I-69; I-70; I-73; I-82; I-88; II-8; II-9; II-10; II-12; II-13; II-15; II-43; II-50; II-51; II-52; II-53; II-84; II-85; II-86; II-87; II-88; II-89; II-90; II-91; II-92; II-93; II-94; II-95; II-96; II-97; II-98; II-99; II-109; II-111; II-115; II-119; II-120; II-121; II-122; II-124; II-128; II-129; II-130; II-131; II-136; III-107; III-109; III-110; III-148; III-153; III-154; III-157; III-164; III-165; III-166; III-167; III-170; III-171; and III-174.

Formula (III)

One embodiment pertains to compounds of Formula (III), or a pharmaceutically acceptable salt thereof,

wherein

-   -   R¹ is selected from the group consisting of hydrogen, OH, CN,         C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the         R¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy         are optionally substituted with one or more substituents         independently selected from the group consisting of R⁷, OR⁷,         SR⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I;         wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl,         C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered         heterocyclyl are optionally substituted with one or more         substituents independently selected from the group consisting of         C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,         C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the         remaining are independently selected from the group consisting         of hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,         C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; or     -   two of R^(2A), R^(2B), R^(2C), an R^(2D) on adjacent carbons         form a fused ring selected from the group consisting of phenyl,         5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl,         and 4-7 membered heterocyclyl; and the remaining are         independently selected from the group consisting of hydrogen,         R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,         C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein the phenyl, 5-6 membered heteroaryl, C₃-C₇         cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of R⁸, OR⁸,         C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH,         CN, NO₂, F, Cl, Br and I;     -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆         alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆         alkenyl, and C₂-C₆ alkynyl are optionally substituted with one         or more substituents independently selected from the group         consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br         and I; wherein the R³ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl are optionally substituted with one or         more substituents independently selected from the group         consisting of R⁹, OR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂,         C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH,         oxo, CN, NO₂, F, Cl, Br and I;     -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆         alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with         one or more substituents independently selected from the group         consisting of R¹⁰, OR¹⁰, SR¹⁰, NHR¹⁰, N(R¹⁰)₂, NH₂, C(O)OH, OH,         oxo, CN, NO₂, F, Cl, Br and I;     -   R^(5A) and R^(5B) are each independently selected from the group         consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆         alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R^(5A) and R^(5B) C₁-C₆         alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are         optionally substituted with one or more substituents         independently selected from the group consisting of 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆         thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5A)         and R^(5B) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; or     -   R^(5A) and R^(5B), together with the carbon atom to which they         are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7         membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic         cycloalkyl and the 4-7 membered monocyclic heterocycle are each         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R^(6A) and R^(6B) are each independently hydrogen;     -   R⁷, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁷         C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F,         Cl, Br and I; wherein each R⁷ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl is optionally substituted with one or more         substituents independently selected from the group consisting of         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo, OH, CN, NO₂, F,         Cl, Br and I;     -   R⁸, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹¹, OR¹¹,         C(O)OR¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl is optionally substituted with one or more         substituents independently selected from the group consisting of         R¹², OR¹², C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, oxo, CN,         NO₂, F, Cl, Br and I;     -   R⁹, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹³, OR¹³,         SR¹³, C(O)R¹³, NHR¹³, N(R¹³)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein each R⁹ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl are optionally substituted with one or         more substituents independently selected from the group         consisting of R¹⁴, OR¹⁴, C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴, SO₂R¹⁴,         NHR¹⁴, N(R¹⁴)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R¹⁰, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹⁰ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of OH, oxo, CN,         NO₂, F, Cl, Br and I; wherein each R¹⁰ C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6         membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R¹¹, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered         aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁         cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹         C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one         or more substituents independently selected from the group         consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each         R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered         heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, F, Cl, Br and I;     -   R¹², at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered         aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁         cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹²         C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one         or more substituents independently selected from the group         consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each         R¹² C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered         heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, F, Cl, Br and I;     -   R¹³, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of OH, oxo, CN,         NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6         membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R¹⁴, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered         heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   with the proviso that R³ is not methyl;     -   with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D)         are each hydrogen, R¹ is not hydrogen;     -   with the proviso that, when R³ is naphthyl, R^(2C) is not         4-(1-methylethyl)phenoxy; and     -   with the proviso that, when R¹ is C₁-alkyl, R³ is not         3-pyridinyl or 4-cyanobenzyl.

In one embodiment of Formula (III), R¹ is selected from the group consisting of hydrogen, OH, CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, SR⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (III), R¹ is selected from the group consisting of hydrogen, CN, and C₁-C₆ alkyl; wherein the R¹ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, N(R⁷)₂, C(O)OH, OH, and CN. In another embodiment of Formula (III), R¹ is hydrogen. In another embodiment of Formula (III), R¹ is CN. In another embodiment of Formula (III), R¹ is C₁-C₆ alkyl; which is unsubstituted. In another embodiment of Formula (III), R¹ is C₁-C₆ alkyl; wherein the R¹ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, N(R⁷)₂, C(O)OH, OH, and CN.

In one embodiment of Formula (III), one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D) are each hydrogen, R¹ is not hydrogen. In another embodiment of Formula (III), one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, F, Cl, and Br; with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D) are each hydrogen, R¹ is not hydrogen. In another embodiment of Formula (III), R^(2A), R^(2B), R^(2C), and R^(2D) are hydrogen; with the proviso that, R¹ is not hydrogen.

In one embodiment of Formula (III), two of R^(2A), R^(2B), R^(2C), and R^(2D) on adjacent carbons form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein the phenyl, 5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (III), R^(2C) and R^(2D) form a 4-7 membered heterocyclyl; and R^(2A) and R^(2B) are independently hydrogen.

In one embodiment of Formula (III), R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (III), R³ is selected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy and phenyl; wherein the R³ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (III), R³ is C₁-C₆ alkyl; wherein the R³ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy and phenyl. In another embodiment of Formula (III), R³ is 6-10 membered aryl; wherein the R³ 6-10 membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (III), R³ is 5-11 membered heteroaryl; wherein the R³ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (III), R³ is C₃-C₁₁ cycloalkyl; wherein the R³ C₃-C₁₁ cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (III), R³ is 4-12 membered heterocyclyl; wherein the R³ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br.

In one embodiment of Formula (III), R⁴ is selected from the group consisting of hydrogen and C₁-C₆ alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹⁰, OR¹⁰, SR¹⁰, NHR¹⁰, N(R¹⁰)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (III), R⁴ is hydrogen. In another embodiment of Formula (III), R⁴ is C₁-C₆ alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with one or more R¹⁰.

In one embodiment of Formula (III), R^(5A) and R^(5B) are each independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R^(5A) and R^(5B) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5A) and R^(5B) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; or R^(5A) and R^(5B), together with the carbon atom to which they are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic cycloalkyl and the 4-7 membered monocyclic heterocycle are each optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (III), R^(5A) and R^(5B) are each independently hydrogen.

In one embodiment of Formula (III), R^(6A) and R^(6B) are each independently hydrogen.

In one embodiment of Formula (III), R⁷, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁷ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (III), R⁷, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁷ C₁-C₆ alkyl is optionally substituted with one or more C₁-C₆ alkoxy; wherein each R⁷ 5-11 membered heteroaryl and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆ haloalkyl, F, and Cl.

In one embodiment of Formula (III), R⁸, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹¹, OR¹¹, C(O)OR¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹², OR¹², C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (III), R⁸, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁸ C₁-C₆ alkyl and C₂-C₆ alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹¹, OR¹¹, C(O)OR¹¹, OH, and F; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹², OR¹², N(R¹²)₂, and F.

In one embodiment of Formula (III), R⁹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹³, OR¹³, SR¹³, C(O)R¹³, NHR¹³, N(R¹³)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴, OR¹⁴, C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴, SO₂R¹⁴, NHR¹⁴, N(R¹⁴)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (III), R⁹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹³, OR¹³, C(O)R¹³, N(R¹³)₂, OH, F, and Cl; wherein each R⁹ 6-10 membered aryl and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴, oxo, and F.

In one embodiment of Formula (III), R¹⁰, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹⁰ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹⁰ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (III), R¹⁰, at each occurrence, is independently C₆-C₁₀ membered aryl; wherein each R¹⁰ C₆-C₁₀ membered aryl is optionally substituted with one or more C₁-C₆ alkoxy.

In one embodiment of Formula (III), R¹¹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹ C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I. In another embodiment of Formula (III), R¹¹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹¹ C₆-C₁₀ membered aryl, is optionally substituted with one or more C₁-C₆ alkoxy.

In one embodiment of Formula (III), R¹², at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹² C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹² C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I. In another embodiment of Formula (III), R¹², at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² C₁-C₆ alkyl is optionally substituted with one or more F; wherein each 4-12 membered heterocyclyl is optionally substituted with one or more C₁-C₆ alkyl.

In one embodiment of Formula (III), R¹³, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In another R¹³, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, and 4-12 membered heterocyclyl; wherein each R¹³ C₆-C₁₀ membered aryl and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, and Cl.

In one embodiment of Formula (III), R¹⁴, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (III), R¹⁴, at each occurrence, is independently C₁-C₆ alkyl; wherein each R¹⁴ C₁-C₆ alkyl is optionally substituted with one or more independently selected 4-12 membered heterocyclyl.

One embodiment pertains to compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is selected from the group consisting of hydrogen, CN, and         C₁-C₆ alkyl; wherein the R¹ C₁-C₆ alkyl is optionally         substituted with one or more substituents independently selected         from the group consisting of R⁷, OR⁷, N(R⁷)₂, C(O)OH, OH, and         CN;     -   one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the         remaining are independently selected from the group consisting         of hydrogen, R⁸, OR⁸, C(O)OR⁸, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH,         CN, F, Cl, and Br; or     -   two of R^(2A), R^(2B), R^(2C), and R^(2D) on adjacent carbons         form a 4-7 membered heterocyclyl; and the remaining are         hydrogen;     -   R³ is selected from the group consisting of C₁-C₆ alkyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and         4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkoxy         and phenyl; wherein the R³ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl and 4-12 membered heterocyclyl are         optionally substituted with one or more substituents         independently selected from the group consisting of R⁹, OR⁹,         C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹,         N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br;     -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆         alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with         one or more R¹⁰;     -   R^(5A) and R^(5B) are each independently selected from the group         consisting of hydrogen and C₁-C₆ alkyl;     -   R^(6A) and R^(6B) are each independently hydrogen;     -   R⁷, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl;         wherein each R⁷ C₁-C₆ alkyl is optionally substituted with one         or more C₁-C₆ alkoxy; wherein each R⁷ 5-11 membered heteroaryl         and 4-12 membered heterocyclyl is optionally substituted with         one or more substituents independently selected from the group         consisting of C₁-C₆ alkoxy, C₁-C₆ haloalkyl, F, and Cl;     -   R⁸, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered         heterocyclyl; wherein each R⁸ C₁-C₆ alkyl and C₂-C₆ alkenyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹¹, OR¹¹,         C(O)OR¹¹, OH, and F; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11         membered heteroaryl and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of R¹², OR¹², N(R¹²)₂ and F;     -   R⁹, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁         cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹         C₁-C₆ alkyl is optionally substituted with one or more         substituents independently selected from the group consisting of         R¹³, OR¹³, C(O)R¹³, N(R¹³)₂, OH, F, and Cl; wherein each R⁹ 6-10         membered aryl and 4-12 membered heterocyclyl are optionally         substituted with one or more substituents independently selected         from the group consisting of R¹⁴, oxo, and F;     -   R¹⁰, at each occurrence, is independently C₆-C₁₀ membered aryl;         wherein each R¹⁰ C₆-C₁₀ membered aryl is optionally substituted         with one or more C₁-C₆ alkoxy;     -   R¹¹, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁         cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹¹         C₆-C₁₀ membered aryl is optionally substituted with one or more         C₁-C₆ alkoxy;     -   R¹², at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁         cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹²         C₁-C₆ alkyl is optionally substituted with one or more F;         wherein each 4-12 membered heterocyclyl is optionally         substituted with one or more C₁-C₆ alkyl;     -   R¹³, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl and 4-12         membered heterocyclyl; wherein each R¹³ C₆-C₁₀ membered aryl and         4-12 membered heterocyclyl is optionally substituted with one or         more substituents independently selected from the group         consisting of C₁-C₆ alkyl and Cl; and     -   R¹⁴, at each occurrence, is independently C₁-C₆ alkyl; wherein         each R¹⁴ C₁-C₆ alkyl is optionally substituted with one or more         4-12 membered heterocyclyl;     -   with the proviso that R³ is not methyl;     -   with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D)         are each hydrogen, R¹ is not hydrogen;     -   with the proviso that, when R³ is naphthyl, R^(2C) is not         4-(1-methylethyl)phenoxy; and     -   with the proviso that, when R¹ is C₁-alkyl, R³ is not         3-pyridinyl or 4-cyanobenzyl.

One embodiment pertains to a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Examples: I-1; I-5; I-6; I-7; I-8; I-13; I-14; I-16; I-17; I-18; I-19; I-20; I-21; I-22; I-23; I-26; I-27; I-28; I-29; I-30; I-31; I-35; I-36; I-37; I-38; I-39; I-42; I-43; I-44; I-46; I-47; I-51; I-52; I-53; I-54; I-55; I-58; I-59; I-66; I-71; I-72; I-74; I-75; I-76; I-77; I-78; I-80; I-81; I-83; I-84; I-85; I-86; I-87; I-89; I-90; I-91; I-92; I-93; I-94; I-95; I-96; I-97; I-98; I-99; I-100; I-101; I-103; I-104; I-105; I-108; I-109; I-117; I-118; I-119; I-122; I-123; I-124; I-125; I-126; I-127; I-128; I-129; I-130; I-131; I-133; I-135; I-138; I-139; I-140; I-141; I-142; I-149; I-151; I-152; I-153; I-154; II-2; II-3; II-4; II-5; II-6; II-18; II-19; II-20; II-21; II-22; II-23; II-24; II-26; II-27; II-28; II-29; II-30; II-31; II-32; II-33; II-34; II-35; II-36; II-37; II-38; II-39; II-40; II-41; II-42; II-44; II-45; II-46; II-47; II-49; II-54; II-55; II-56; II-57; II-58; II-59; II-60; II-61; II-62; II-63; II-64; II-65; II-66; II-67; II-69; II-70; II-71; II-72; II-73; II-74; II-75; II-76; II-77; II-78; II-79; II-80; II-81; II-82; II-83; II-100; II-101; II-102; II-103; II-104; II-105; II-106; II-107; II-108; II-110; II-112; II-113; II-116; II-117; II-123; II-125; II-126; II-127; II-132; II-133; II-134; II-135; III-3; III-4; III-5; III-6; III-9; III-11; III-12; III-13; III-14; III-15; III-16; III-17; III-18; III-19; III-20; III-21; III-22; III-23; III-24; III-25; III-26; III-27; III-28; III-29; III-30; III-31; III-32; III-33; III-34; III-35; III-36; III-37; III-38; III-39; III-40; III-41; III-42; III-43; III-44; III-45; III-46; III-47; III-48; III-49; III-50; III-51; III-52, III-53; III-54; III-55; III-56; III-57; III-58; III-59; III-60; III-61; III-62; III-63; III-64; III-65; III-66; III-67; III-68; III-69; III-70; III-71; III-72; III-73; III-74; III-75; III-76; III-77; III-78; III-79; III-80; III-81; III-82; III-83; III-84; III-85; III-86; III-87; III-88; III-89; III-90; III-91; III-92; III-93; III-94; III-95; III-96; III-97; III-98; III-99; III-100; III-101; III-102; III-103; III-104; III-105; III-106; III-108; III-111; III-112; III-113; III-114; III-115; III-116; III-117; III-118; III-119; III-120 III-121; III-122; III-123; III-124; III-125; III-126; III-127; III-128; III-129; III-130; III-131; III-132; III-33; III-134; III-135; III-136; III-137; III-138; III-139; III-140; III-141; III-142; III-143; III-144; III-145; III-146; III-147; III-149; III-150; III-151; III-152; III-155; III-156; III-158; III-159; III-160; III-161; III-162; III-163; III-168; III-169; III-172; III-173; III-179; III-181; III-182; III-183; III-184; III-185; III-186; III-187; and III-188.

Formula (IV)

One embodiment pertains to compounds of Formula (IV), or a pharmaceutically acceptable salt thereof,

wherein

-   -   R¹ is selected from the group consisting of hydrogen, OH, CN,         C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the         R¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy         are optionally substituted with one or more substituents         independently selected from the group consisting of R⁷, OR⁷,         SR⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I;         wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl,         C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered         heterocyclyl are optionally substituted with one or more         substituents independently selected from the group consisting of         C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,         C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the         remaining are independently selected from the group consisting         of hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,         C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; or     -   two of R^(2A), R^(2B), R^(2C), an R^(2D) on adjacent carbons         form a fused ring selected from the group consisting of phenyl,         5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl,         and 4-7 membered heterocyclyl; and the remaining are         independently selected from the group consisting of hydrogen,         R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,         C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein the phenyl, 5-6 membered heteroaryl, C₃-C₇         cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl         are optionally substituted with one or more substituents         independently selected from the group consisting of R⁸, OR⁸,         C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH,         CN, NO₂, F, Cl, Br and I;     -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆         alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆         alkenyl, and C₂-C₆ alkynyl are optionally substituted with one         or more substituents independently selected from the group         consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br         and I; wherein the R³ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl are optionally substituted with one or         more substituents independently selected from the group         consisting of R⁹, OR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂,         C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH,         oxo, CN, NO₂, F, Cl, Br and I;     -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆         alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with         one or more substituents independently selected from the group         consisting of R¹⁰, OR¹⁰, SR¹⁰, NHR¹⁰, N(R¹⁰)₂, NH₂, C(O)OH, OH,         oxo, CN, NO₂, F, Cl, Br and I;     -   R^(6A) and R^(6B) are each independently hydrogen;     -   R⁷, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁷         C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F,         Cl, Br and I; wherein each R⁷ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl is optionally substituted with one or more         substituents independently selected from the group consisting of         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo, OH, CN, NO₂, F,         Cl, Br and I;     -   R⁸, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein         each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹¹, OR¹¹,         C(O)OR¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br         and I; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12         membered heterocyclyl is optionally substituted with one or more         substituents independently selected from the group consisting of         R¹², OR¹², C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, oxo, CN,         NO₂, F, Cl, Br and I;     -   R⁹, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁹         C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally         substituted with one or more substituents independently selected         from the group consisting of R¹³, OR¹³, SR¹³, C(O)R¹³, NHR¹³,         N(R¹³)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein each R⁹         6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,         C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are         optionally substituted with one or more substituents         independently selected from the group consisting of R¹⁴, OR¹⁴,         C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴, SO₂R¹⁴, NHR¹⁴, N(R¹⁴)₂, NH₂,         C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   R¹⁰, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹⁰ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of OH, oxo, CN,         NO₂, F, Cl, Br and I; wherein each R¹⁰ C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6         membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I;

R¹¹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹ C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I;

-   -   R¹², at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered         aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁         cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹²         C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one         or more substituents independently selected from the group         consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each         R¹² C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered         heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, F, Cl, Br and I;     -   R¹³, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of OH, oxo, CN,         NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁         cycloalkenyl, and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6         membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; and     -   R¹⁴, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁         cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;         wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl         is optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered         heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I;     -   with the proviso that R³ is not methyl;     -   with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D)         are each hydrogen, R¹ is not hydrogen;     -   with the proviso that, when R³ is naphthyl, R^(2C) is not         4-(1-methylethyl)phenoxy; and     -   with the proviso that, when R¹ is C₁-alkyl, R³ is not         3-pyridinyl or 4-cyanobenzyl.

In one embodiment of Formula (IV), R¹ is selected from the group consisting of hydrogen, OH, CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, SR⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (IV), R¹ is selected from the group consisting of hydrogen, CN, and C₁-C₆ alkyl; wherein the R¹ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, N(R⁷)₂, C(O)OH, OH, and CN. In another embodiment of Formula (IV), R¹ is hydrogen. In another embodiment of Formula (IV), R¹ is CN. In another embodiment of Formula (IV), R¹ is C₁-C₆ alkyl; which is unsubstituted. In another embodiment of Formula (IV), R¹ is C₁-C₆ alkyl; wherein the R¹ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, N(R⁷)₂, C(O)OH, OH, and CN.

In one embodiment of Formula (IV), one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D) are each hydrogen, R¹ is not hydrogen. In another embodiment of Formula (IV), one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, F, Cl, and Br; with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D) are each hydrogen, R¹ is not hydrogen. In another embodiment of Formula (IV), R^(2A), R^(2B), R^(2C), and R^(2D) are hydrogen; with the proviso that, R¹ is not hydrogen.

In one embodiment of Formula (IV), two of R^(2A), R^(2B), R^(2C), and R^(2D) on adjacent carbons form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein the phenyl, 5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (IV), R^(2C) and R^(2D) form a 4-7 membered heterocyclyl; and R^(2A) and R^(2B) are independently hydrogen.

In one embodiment of Formula (IV), R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (IV), R³ is selected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy and phenyl; wherein the R³ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (IV), R³ is C₁-C₆ alkyl; wherein the R³ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy and phenyl. In another embodiment of Formula (IV), R³ is 6-10 membered aryl; wherein the R³ 6-10 membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (IV), R³ is 5-11 membered heteroaryl; wherein the R³ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (IV), R³ is C₃-C₁₁ cycloalkyl; wherein the R³ C₃-C₁₁ cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br. In another embodiment of Formula (IV), R³ is 4-12 membered heterocyclyl; wherein the R³ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br.

In one embodiment of Formula (IV), R⁴ is selected from the group consisting of hydrogen and C₁-C₆ alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹⁰, OR¹⁰, SR¹⁰, NHR¹⁰, N(R¹⁰)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (IV), R⁴ is hydrogen. In another embodiment of Formula (IV), R⁴ is C₁-C₆ alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with one or more R¹⁰.

In one embodiment of Formula (IV), R^(6A) and R^(6B) are each independently hydrogen.

In one embodiment of Formula (IV), R⁷, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁷ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (IV), R⁷, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁷ C₁-C₆ alkyl is optionally substituted with one or more C₁-C₆ alkoxy; wherein each R⁷ 5-11 membered heteroaryl and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆ haloalkyl, F, and Cl.

In one embodiment of Formula (IV), R⁸, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹¹, OR¹¹, C(O)OR¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹², OR¹², C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (IV), R⁸, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁸ C₁-C₆ alkyl and C₂-C₆ alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹¹, OR¹¹, C(O)OR¹¹, OH, and F; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹², OR¹², N(R¹²)₂, and F.

In one embodiment of Formula (IV), R⁹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹³, OR¹³, SR¹³, C(O)R¹³, NHR¹³, N(R¹³)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴, OR¹⁴, C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹, SO₂R¹⁴, NHR¹⁴, N(R¹⁴)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (IV), R⁹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹³, OR¹³, C(O)R¹³, N(R¹³)₂, OH, F, and Cl; wherein each R⁹ 6-10 membered aryl and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴, oxo, and F.

In one embodiment of Formula (IV), R¹⁰, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹⁰ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹⁰ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (IV), R¹⁰, at each occurrence, is independently C₆-C₁₀ membered aryl; wherein each R¹⁰ C₆-C₁₀ membered aryl is optionally substituted with one or more C₁-C₆ alkoxy.

In one embodiment of Formula (IV), R¹¹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹ C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I. In another embodiment of Formula (IV), R¹¹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹¹ C₆-C₁₀ membered aryl is optionally substituted with one or more C₁-C₆ alkoxy.

In one embodiment of Formula (IV), R¹², at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹² C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹² C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I. In another embodiment of Formula (IV), R¹², at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹² C₁-C₆ alkyl is optionally substituted with one or more F; wherein each 4-12 membered heterocyclyl is optionally substituted with one or more C₁-C₆ alkyl.

In one embodiment of Formula (IV), R¹³, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In another R¹³, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, and 4-12 membered heterocyclyl; wherein each R¹³ C₆-C₁₀ membered aryl and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, and Cl.

In one embodiment of Formula (IV), R¹⁴, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment of Formula (IV), R¹⁴, at each occurrence, is independently C₁-C₆ alkyl; wherein each R¹⁴ C₁-C₆ alkyl is optionally substituted with one or more independently selected 4-12 membered heterocyclyl.

One embodiment pertains to compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is selected from the group consisting of hydrogen, CN, and         C₁-C₆ alkyl; wherein the R¹ C₁-C₆ alkyl is optionally         substituted with one or more substituents independently selected         from the group consisting of R⁷, OR⁷, N(R⁷)₂, C(O)OH, OH, and         CN;     -   one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the         remaining are independently selected from the group consisting         of hydrogen, R⁸, OR⁸, C(O)OR⁸, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH,         CN, F, Cl, and Br; or     -   two of R^(2A), R^(2B), R^(2C), and R^(2D) on adjacent carbons         form a 4-7 membered heterocyclyl; and the remaining are         hydrogen;     -   R³ is selected from the group consisting of C₁-C₆ alkyl, 6-10         membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and         4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl is         optionally substituted with one or more substituents         independently selected from the group consisting of C₁-C₆ alkoxy         and phenyl; wherein the R³ 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl and 4-12 membered heterocyclyl are         optionally substituted with one or more substituents         independently selected from the group consisting of R⁹, OR⁹,         C(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹,         N(R⁹)₂, NH₂, OH, oxo, CN, NO₂, F, Cl, and Br;     -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆         alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with         one or more R¹⁶;     -   R^(6A) and R^(6B) are each independently hydrogen;     -   R⁷, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, 6-10 membered aryl, 5-11 membered         heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl;         wherein each R⁷ C₁-C₆ alkyl is optionally substituted with one         or more C₁-C₆ alkoxy; wherein each R⁷ 5-11 membered heteroaryl         and 4-12 membered heterocyclyl is optionally substituted with         one or more substituents independently selected from the group         consisting of C₁-C₆ alkoxy, C₁-C₆ haloalkyl, F, and Cl;     -   R⁸, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₆-C₁₀ membered aryl,         5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered         heterocyclyl; wherein each R⁸ C₁-C₆ alkyl and C₂-C₆ alkenyl is         optionally substituted with one or more substituents         independently selected from the group consisting of R¹¹, OR¹¹,         C(O)OR¹¹, OH, and F; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11         membered heteroaryl and 4-12 membered heterocyclyl is optionally         substituted with one or more substituents independently selected         from the group consisting of R¹², OR¹², N(R¹²)₂ and F;     -   R⁹, at each occurrence, is independently selected from the group         consisting of C₁-C₆ alkyl, 6-10 membered aryl, C₃-C₁₁         cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁹         C₁-C₆ alkyl is optionally substituted with one or more         substituents independently selected from the group consisting of         R¹³, OR¹³, C(O)R¹³, N(R¹³)₂, OH, F, and Cl; wherein each R⁹ 6-10         membered aryl and 4-12 membered heterocyclyl are optionally         substituted with one or more substituents independently selected         from the group consisting of R¹⁴, oxo, and F;     -   R¹⁰, at each occurrence, is independently C₆-C₁₀ membered aryl;         wherein each R¹⁰ C₆-C₁₀ membered aryl is optionally substituted         with one or more C₁-C₆ alkoxy;

R¹¹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹¹ C₆-C₁₀ membered aryl is optionally substituted with one or more C₁-C₆ alkoxy;

-   -   R¹², at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl, C₃-C₁₁         cycloalkyl, and 4-12 membered heterocyclyl; wherein each R¹²         C₁-C₆ alkyl is optionally substituted with one or more F;         wherein each 4-12 membered heterocyclyl is optionally         substituted with one or more C₁-C₆ alkyl;     -   R¹³, at each occurrence, is independently selected from the         group consisting of C₁-C₆ alkyl, C₆-C₁₀ membered aryl and 4-12         membered heterocyclyl; wherein each R¹³ C₆-C₁₀ membered aryl and         4-12 membered heterocyclyl is optionally substituted with one or         more substituents independently selected from the group         consisting of C₁-C₆ alkyl and Cl; and     -   R¹⁴, at each occurrence, is independently C₁-C₆ alkyl; wherein         each R¹⁴ C₁-C₆ alkyl is optionally substituted with one or more         4-12 membered heterocyclyl;     -   with the proviso that R³ is not methyl;     -   with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D)         are each hydrogen, R¹ is not hydrogen;     -   with the proviso that, when R³ is naphthyl, R^(2C) is not         4-(1-methylethyl)phenoxy; and     -   with the proviso that, when R¹ is C₁-alkyl, R³ is not         3-pyridinyl or 4-cyanobenzyl.

One embodiment pertains to a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Examples: I-79, I-102; I-106; I-107; I-114: I-132; I-134; I-136; I-137; I-143; I-144; I-145: I-146; I-147: I-148; I-155; II-114; II-118; III-175; and III-177.

Compounds of the invention were named using Name 2016.1.1 (File Version N30E41, Build 86668, 25 May, 2016) naming algorithm by Advanced Chemical Development, Inc., or Struct=Name naming algorithm as part of CHEMDRAW® ULTRA v. 12.0.2.1076 or Professional Version 15.0.0.106.

Compounds of the invention may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The invention contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by precipitation or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry”, 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods.

Compounds of the invention may exist as cis or trans isomers, wherein substituents on a ring may attached in such a manner that they are on the same side of the ring (cis) relative to each other, or on opposite sides of the ring relative to each other (trans). For example, cyclobutane may be present in the cis or trans configuration, and may be present as a single isomer or a mixture of the cis and trans isomers. Individual cis or trans isomers of compounds of the invention may be prepared synthetically from commercially available starting materials using selective organic transformations, or prepared in single isomeric form by purification of mixtures of the cis and trans isomers. Such methods are well-known to those of ordinary skill in the art, and may include separation of isomers by precipitation or chromatography.

It should be understood that the compounds of the invention may possess tautomeric forms, as well as geometric isomers, and that these also constitute an aspect of the invention.

The present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of Formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S. Certain isotopically-labelled compounds of Formula (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formula (I) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

Thus, the formula drawings within this specification can represent only one of the possible tautomeric, geometric, or stereoisomeric forms. It is to be understood that the invention encompasses any tautomeric, geometric, or stereoisomeric form, and mixtures thereof, and is not to be limited merely to any one tautomeric, geometric, or stereoisomeric form utilized within the formula drawings.

Compounds of Formula (I) may be used in the form of pharmaceutically acceptable salts. The phrase “pharmaceutically acceptable salt” means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts have been described in S. M. Berge et al. J. Pharmaceutical Sciences, 1977, 66: 1-19.

Compounds of Formula (I) may contain either a basic or an acidic functionality, or both, and can be converted to a pharmaceutically acceptable salt, when desired, by using a suitable acid or base. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention.

Examples of acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid, and citric acid.

Basic addition salts may be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other examples of organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.

The term “pharmaceutically acceptable prodrug” or “prodrug” as used herein, refers to derivatives of the compounds of the invention which have cleavable groups. Such derivatives become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo. Prodrugs of the compounds of the invention are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.

The invention contemplates compounds of Formula (I) formed by synthetic means or formed by in vivo biotransformation of a prodrug.

Compounds described herein may exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.

Pharmaceutical Compositions

When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. The phrase “pharmaceutical composition” refers to a composition suitable for administration in medical or veterinary use.

The pharmaceutical compositions that comprise a compound of Formula (I), alone or in combination with further therapeutically active ingredient, may be administered to the subjects orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term “parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which may serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.

Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate), and suitable mixtures thereof. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it may be desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release may be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, solid dosage forms may contain from 1% to 95% (w/w) of a compound of Formula (I). In certain embodiments, the compound of Formula (I), or pharmaceutically acceptable salts thereof, may be present in the solid dosage form in a range of from 5% to 70% (w/w). In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable carrier, such as sodium citrate or dicalcium phosphate and/or a), fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

The pharmaceutical composition may be a unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampules. Also, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or it may be the appropriate number of any of these in packaged form. The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to 95% (w/w) of a unit dose, according to the particular application and the potency of the active component. The composition may, if desired, also contain other compatible therapeutic agents.

The dose to be administered to a subject may be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the subject to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a particular subject. In determining the effective amount of the compound to be administered in the treatment or prophylaxis of the disorder being treated, the physician may evaluate factors such as the circulating plasma levels of the compound, compound toxicities, and/or the progression of the disease, etc.

For administration, compounds may be administered at a rate determined by factors that may include, but are not limited to, the LD₅₀ of the compound, the pharmacokinetic profile of the compound, contraindicated drugs, and the side-effects of the compound at various concentrations, as applied to the mass and overall health of the subject. Administration may be accomplished via single or divided doses.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan and mixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compounds with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Compounds may also be administered in the form of liposomes. Liposomes generally may be derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to a compound of the invention, stabilizers, preservatives, excipients, and the like. Examples of lipids include, but are not limited to, natural and synthetic phospholipids, and phosphatidyl cholines (lecithins), used separately or together.

Methods to form liposomes have been described, see example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound described herein include powders, sprays, ointments, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

A compound of the invention may also be administered in sustained release forms or from sustained release drug delivery systems.

Methods of Use

The compounds and compositions using any amount and any route of administration may be administered to a subject for the treatment or prevention of cystic fibrosis, pancreatic insufficiency, Sjögren's syndrome (SS), chronic obstructive lung disease (COLD), or chronic obstructive airway disease (COAD).

The term “administering” refers to the method of contacting a compound with a subject. Thus, the compounds may be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, parentally, or intraperitoneally. Also, the compounds described herein may be administered by inhalation, for example, intranasally. Additionally, the compounds may be administered transdermally, topically, and via implantation. In certain embodiments, the compounds and compositions thereof may be delivered orally. The compounds may also be delivered rectally, bucally, intravaginally, ocularly, or by insufflation. CFTR-modulated disorders and conditions may be treated prophylactically, acutely, and chronically using compounds and compositions thereof, depending on the nature of the disorder or condition. Typically, the host or subject in each of these methods is human, although other mammals may also benefit from the administration of compounds and compositions thereof as set forth hereinabove.

Compounds of the invention are useful as modulators of CFTR. Thus, the compounds and compositions are particularly useful for treating or lessening the severity or progression of a disease, disorder, or a condition where hyperactivity or inactivity of CFTR is involved. Accordingly, the invention provides a method for treating cystic fibrosis, pancreatic insufficiency, Sjögren's syndrome (SS), chronic obstructive lung disease (COLD), or chronic obstructive airway disease (COAD) in a subject, wherein the method comprises the step of administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a preferred embodiment thereof as set forth above, with or without a pharmaceutically acceptable carrier. Particularly, the method is for the treatment or prevention of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.

In a particular embodiment, the present invention provides compounds of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions comprising a compound of the invention, for use in the treatment of cystic fibrosis, pancreatic insufficiency, Sjögren's syndrome (SS), chronic obstructive lung disease (COLD) or chronic obstructive airway disease (COAD). In a more particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.

One embodiment is directed to the use of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament. The medicament optionally can comprise one or more additional therapeutic agents. In some embodiments, the medicament is for use in the treatment of cystic fibrosis, pancreatic insufficiency, Sjögren's syndrome (SS), chronic obstructive lung disease (COLD) or chronic obstructive airway disease (COAD). In a particular embodiment, the medicament is for use in the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.

This invention also is directed to the use of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. The medicament optionally can comprise one or more additional therapeutic agents. In a particular embodiment, the invention is directed to the use of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.

In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In another embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers. In another embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents wherein the additional therapeutic agents are CFTR modulators.

In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, one potentiator, and one or more additional correctors. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a cystic fibrosis treatment agent. In one embodiment, the present invention provides a method for treating cystic fibrosis in a subject comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In another embodiment, the present invention provides a method for treating cystic fibrosis in a subject comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers. In one embodiment, the present invention provides a method for treating cystic fibrosis in a subject comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents wherein the additional therapeutic agents are CFTR modulators. In one embodiment, the present invention provides a method for treating cystic fibrosis in a subject comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof, and, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a cystic fibrosis treatment agent. In one embodiment, the present invention provides a method for treating cystic fibrosis in a subject comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. In a particular embodiment, the additional therapeutic agent(s) are one potentiator, and one or more additional correctors. In another embodiment, the additional therapeutic agent(s) is selected from the group consisting of CFTR modulators and CFTR amplifiers. In another embodiment, the other therapeutic agent(s) is a CFTR modulator. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.

The present compounds or pharmaceutically acceptable salts thereof may be administered as the sole active agent or it may be co-administered with other therapeutic agents, including other compounds or pharmaceutically acceptable salts thereof, that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. The present compounds may be co-administered to a subject. The term “co-administered” means the administration of two or more different therapeutic agents to a subject in a single pharmaceutical composition or in separate pharmaceutical compositions. Thus co-administration involves administration at the same time of a single pharmaceutical composition comprising two or more therapeutic agents or administration of two or more different compositions to the same subject at the same or different times.

The compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with a therapeutically effective amount of one or more additional therapeutic agents to treat a CFTR mediated disease, where examples of the therapeutic agents include, but are not limited to antibiotics (for example, aminoglycosides, colistin, aztreonam, ciprofloxacin, and azithromycin), expectorants (for example, hypertonic saline, acetylcysteine, dornase alfa, and denufosol), pancreatic enzyme supplements (for example, pancreatin, and pancrelipase), epithelial sodium channel blocker (ENaC) inhibitors, CFTR modulators (for example, CFTR potentiators, CFTR correctors), and CFTR amplifiers. In one embodiment, the CFTR mediated disease is cystic fibrosis, chronic obstructive pulmonary disease (COPD), dry eye disease, pancreatic insufficiency, or Sjögren's syndrome. In one embodiment, the CFTR mediated disease is cystic fibrosis. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or two CFTR modulators and one CFTR amplifier. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator, one or more correctors, and one CFTR amplifier. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or more CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with two CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with three CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator and one or more correctors. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator and two correctors. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or more correctors. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one corrector. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with two correctors.

Examples of CFTR potentiators include, but are not limited to, Ivacaftor (VX-770), CTP-656, NVS-QBW251, FD1860293, GLPG2451, GLPG3067, GLPG1837, PTI-808, N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide, and 3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide. Examples of potentiators are also disclosed in publications: WO2005120497, WO2008147952, WO2009076593, WO2010048573, WO2006002421, WO2008147952, WO2011072241, WO2011113894, WO2013038373, WO2013038378, WO2013038381, WO2013038386, WO2013038390, WO2014180562, WO2015018823, WO2014/180562, WO2015018823, WO 2016193812 and WO2017208115.

In one embodiment, the potentiator can be selected from the group consisting of

-   Ivacaftor (VX-770,     N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide); -   GLPG1837; -   GLP-2451; -   PTI-808; -   CTP-656; -   NVS-QBW251, -   FD1860293 -   GLPG3067; -   2-(2-fluorobenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide; -   2-(2-hydroxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide -   2-(1-hydroxycyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide; -   5,5,7,7-tetramethyl-2-(2-(trifluoromethyl)benzamido)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide; -   2-(2-hydroxy-2-methylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide; -   2-(1-(hydroxymethyl)cyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide; -   2-(3-hydroxy-2,2-dimethylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-methyl-1H-pyrazole-3-carboxamide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-cyclopropyl-1H-pyrazole-3-carboxamide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-isopropyl-1H-pyrazole-3-carboxamide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide; -   5-tert-butyl-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-ethyl-1H-pyrazole-3-carboxamide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-3-ethyl-4-methyl-1H-pyrazole-5-carboxamide; -   2-(2-hydroxypropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-1H-pyrazole-3-carboxamide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide; -   4-bromo-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-methyl-1H-pyrazole-3-carboxamide; -   2-(2-hydroxy-3,3-dimethylbutanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide; -   2-[(2-hydroxy-4-methyl-pentanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide; -   5-(2-methoxy-ethoxy)-1H-pyrazole-3-carboxylic acid     (3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-amide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(3-methoxypropyl)-1H-pyrazole-3-carboxamide; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2-ethoxyethyl)-1H-pyrazole-3-carboxamide; -   2-[[(2S)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide; -   2-[[(2R)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide; -   2-[(2-hydroxy-2,3,3-trimethyl-butanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide; -   [5-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl     dihydrogen phosphate; -   [3-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl     dihydrogen phosphate; -   N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(1,4-dioxan-2-yl)-1H-pyrazole-3-carboxamide; -   5,5,7,7-tetramethyl-2-[[(2S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanoyl]amino]-4H-thieno[2,3-c]pyran-3-carboxamide; -   2-[[(2S)-2-hydroxypropanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide; -   3-amino-N-(2-hydroxy-2-methylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide; -   3-amino-N-[(4-hydroxy-1-methylpiperidin-4-yl)methyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide; -   3-amino-N-(3-hydroxy-2,2-dimethylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide; -   3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(1-hydroxycyclopropyl)methyl]pyridine-2-carboxamide; -   3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]pyridine-2-carboxamide; -   3-amino-5-[(3-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-methylpropyl)pyridine-2-carboxamide; -   3-amino-N-[2-(cyclopropylamino)-2-oxoethyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide; -   (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(azetidin-1-yl)methanone; -   (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-(hydroxymethyl)azetidin-1-yl]methanone; -   (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-fluoroazetidin-1-yl)methanone; -   3-amino-N-[(2R)-2-hydroxy-3-methoxypropyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide; -   (3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone; -   (3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone; -   rac-3-amino-N-[(3R,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide; -   3-amino-5-[(4,4-difluoropiperidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide; -   (3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone; -   3-amino-N-(2-hydroxy-4-methylpentyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide; -   (3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone; -   3-amino-N-(3,3,3-trifluoro-2-hydroxypropyl)-5-{[4-(trifluoromethyl)piperidin-1-yl]sulfonyl}pyridine-2-carboxamide; -   3-amino-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide; -   3-amino-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide; -   3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2S)-2-hydroxypropyl]pyridine-2-carboxamide; -   3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2R)-2-hydroxy-3-methoxypropyl]pyridine-2-carboxamide; -   3-amino-N-[2-oxo-2-(propan-2-ylamino)ethyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide; -   (3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone; -   3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3R)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide; -   (3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone; -   3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3S)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide; -   3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}-N-[(3S)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide; -   3-amino-N-[2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide; -   3-amino-N-(3-tert-butoxy-2-hydroxypropyl)-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide; -   [3-amino-5-(phenylsulfonyl)pyridin-2-yl][3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone; -   {3-amino-5-[(3-fluorophenyl)sulfonyl]pyridin-2-yl}[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;     and -   3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide.

Non-limiting examples of correctors include Lumacaftor (VX-809), 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide (VX-661), VX-983, GLPG2851, GLPG2222, GLPG2665, GLPG2737, GLPG3221, PTI-801, VX-152, VX-440, VX-445, VX-659, FDL169, FDL304, FD2052160, and FD2035659. Examples of correctors are also disclosed in WO2016069757, WO2016069891, WO2017009804, WO2017060874, WO2017060873, WO2017187321 and U.S. patent application Ser. Nos. 15/723,896, 15/726,075 and PCT Patent Application No. PCT/IB2017/058179.

In one embodiment, the corrector(s) can be selected from the group consisting of

-   Lumacaftor (VX-809); -   1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide     (VX-661); -   PTI-801; -   VX-983; -   GLPG2665; -   GLPG2851; -   GLPG2222; -   GLPG2737; -   GLPG3221; -   VX-152; -   VX-440; -   VX-659; -   VX-445; -   FDL169 -   FDL304; -   FD2052160; -   FD2035659; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   3-({3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoyl}amino)-1-methylcyclopentanecarboxylic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(2R)-2,3-dihydroxypropyl]benzamide; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(2-methoxyethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   3-[(2R,4R)-7-(benzyloxy)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(2-fluoroethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic     acid; -   4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-8-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic     acid; -   rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic     acid; -   rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic     acid; -   3-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic     acid; -   3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic     acid; -   rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic     acid; -   3-[(2S,4R,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic     acid; -   3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic     acid; -   4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic     acid; -   3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic     acid; -   3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic     acid; -   5-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]pyrazine-2-carboxylic     acid; -   6-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]pyridine-3-carboxylic     acid; -   trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic     acid; -   6-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]pyridine-3-carboxylic     acid; -   trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic     acid; -   ethyl     trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylate; -   cis-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic     acid; -   trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic     acid; -   1-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclopropane-1-carboxylic     acid; -   trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic     acid; -   trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic     acid; -   trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic     acid; -   trans-4-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic     acid; and -   trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic     acid.

In one embodiment, the additional therapeutic agent is a CFTR amplifier. CFTR amplifiers enhance the effect of known CFTR modulators, such as potentiators and correctors. Examples of CFTR amplifiers are PTI130 and PTI-428. Examples of amplifiers are also disclosed in International Patent Publication Nos.: WO2015138909 and WO2015138934.

In one embodiment, the additional therapeutic agent is a CFTR stabilizer. CFTR stabilizers enhance the stability of corrected CFTR that has been treated with a corrector, corrector/potentiator or other CFTR modulator combination(s). An example of a CFTR stabilizer is cavosonstat (N91115). Examples of stabilizers are also disclosed in International Patent Publication No.: WO2012048181.

In one embodiment, the additional therapeutic agent is an agent that reduces the activity of the epithelial sodium channel blocker (ENaC) either directly by blocking the channel or indirectly by modulation of proteases that lead to an increase in ENaC activity (e.g., serine proteases, channel-activating proteases). Exemplary of such agents include camostat (a trypsin-like protease inhibitor), QAU145, 552-02, GS-9411, INO-4995, Aerolytic, amiloride, and VX-371. Additional agents that reduce the activity of the epithelial sodium channel blocker (ENaC) can be found, for example, in International Patent Publication Nos. WO2009074575 and WO2013043720; and U.S. Pat. No. 8,999,976.

In one embodiment, the ENaC inhibitor is VX-371.

In one embodiment, the ENaC inhibitor is SPX-101 (S18).

In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In a particular embodiment, the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers. In a further embodiment, the additional therapeutic agents are CFTR modulators. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, one potentiator, and one or more additional correctors.

The present invention also is directed to kits that comprise one or more compounds and/or salts of the invention, and, optionally, one or more additional therapeutic agents.

The present invention also is directed to methods of use of the compounds, salts, compositions, and/or kits of the invention to, with or without one or more additional therapeutic agents, for example, modulate the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, and treat a disease treatable by modulating the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein (including cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease).

Chemical Synthetic Procedures General

The compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) were given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Protective Groups in Organic Synthesis Third Edition; Greene, T W and Wuts, P G M, Eds.; Wiley-Interscience: New York, 1991).

The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

All reagents were of commercial grade and were used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Column chromatography was performed on silica gel 60 (35-70 μm). Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). ¹H NMR spectra were recorded on a Bruker Advance 300 NMR spectrometer (300 MHz), an Agilent 400 MHz NMR spectrometer or a 500 MHz spectrometer. Chemical shifts (δ) for ¹H NMR spectra were reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, i.e. CHCl₃ (δ 7.27), as internal reference. Multiplicities were given as singlet (s), doublet (d), doublet of doublets of doublets (ddd), doublet of doublets of doublets of doublets (dddd), doublet of doublets of quartets (ddq), doublet of doublets of triplets (ddt), doublet of quartets (dq), doublet of triplets of doublets (dtd), heptet (hept), triplet (t), triplet of doublets of doublets (tdd), triplet of quartets (tq), quartet (q), quartet of doublets (qd), quartet of triplets (qt), quintuplet (quin), multiplet (m) and broad (br). Electrospray MS spectra were obtained on a Waters platform LC/MS spectrometer or with Waters Acquity H-Class UPLC coupled to a Waters Mass detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×50 mm L, Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×30 mm L, or Waters Xterra® MS 5 μm C18, 100×4.6 mm. The methods were using either MeCN/H₂O gradients (H₂O contains either 0.1% TFA or 0.1% NH₃) or CH₃OH/H₂O gradients (H₂O contains 0.05% TFA). Microwave heating was performed with a Biotage® Initiator.

Racemic mixtures were separated on an Agilent HP1100 system with UV detection. Column used: Chiralpak® IA (10×250 mm, 5 μm). Solvents used: iPrOH and tBME. Enantiomeric purity was determined on an Agilent HP1100 system with UV detection. Column used: Chiralpak® IA (4.6×250 mm, 5 μm). Solvents used: iPrOH and tBME.

Reverse Phase Purification Methods Prep LC/MS Method TFA6

Samples were purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 um 100 Å AXIA™ column (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minute 15% A, 0.5-8.0 minute linear gradient 15-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1 minute linear gradient 100-15% A, 9.1-10 minute 15% A). A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method TFA7

Samples were purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 um 100 Å AXIA™ column (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minute 25% A, 0.5-8.0 minute linear gradient 25-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1 minute linear gradient 100-25% A, 9.1-10 minute 25% A). A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method TFA8

Samples were purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 um 100 Å AXIA™ column (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minute 35% A, 0.5-8.0 minute linear gradient 35-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1 minute linear gradient 100-35% A, 9.1-10 minute 35% A). A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method TFA10

Samples were purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 um 100 Å AXIA™ column (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 30 mL/minute (0-0.2 minute 5% A, 0.2-3.0 minute linear gradient 5-100% A, 4.1-4.5 minute 100-5% A, 4.5-5.0 minute 5% A). A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method AA6

Samples were purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 um 100 Å AXIA™ column (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minute 15% A, 0.5-8.0 minute linear gradient 15-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1 minute linear gradient 100-15% A, 9.1-10 minute 15% A). A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method AA7

Samples were purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 um 100 Å AXIA™ column (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minute 25% A, 0.5-8.0 minute linear gradient 25-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1 minute linear gradient 100-25% A, 9.1-10 minute 25% A). A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method AA8

Samples were purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 um 100 Å AXIA™ column (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minute 35% A, 0.5-8.0 minute linear gradient 35-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1 minute linear gradient 100-35% A, 9.1-10 minute 35% A). A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

Stereochemistry of final compounds was arbitrarily assigned in some cases, based on the order of elution and/or activity with respect to existing analogs.

List of abbreviations used in the experimental section:

Abbreviation Definition MeCN acetonitrile TFA trifluoroacetic acid NMR nuclear magnetic resonance DMSO dimethyl sulfoxide LC/MS or LCMS liquid chromatography-mass spectrometry MeOH methanol tBME tert-butyl methyl ether s singlet br s broad singlet d duplet or doublet dd double duplet or doublet of doublets m multiplet min minute mL milliliter μL microliter g gram mg milligram mmol millimoles HPLC high pressure liquid chromatography Ppm parts per million μm micrometer

Synthetic Preparation of the Compounds of the Invention Schemes

The compounds of the present disclosure can be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds can be prepared. The compounds of this disclosure can be prepared by a variety of synthetic procedures.

Compounds of formula (7), which are representative of compounds of Formula (I), can be prepared as described in Scheme 1. A mixture of toluenesulfonylmethyl isocyanide and a compound of formula (1), wherein X¹, X², X³, X⁴, R^(5A), R^(5B), R^(6A), and R^(6B) are as described herein, can be treated with potassium tert-butoxide to provide compounds of formula (2). The addition is typically performed under an inert atmosphere at low temperature, and in a solvent such as, but not limited to, dimethoxyethane, before warming up to ambient temperature. Compounds of formula (2) can be treated with a solution of aqueous sodium or lithium hydroxide to provide compounds of formula (3). The reaction is typically performed at an elevated temperature in a solvent such as, but not limited to, ethanol. Alternatively, compounds of formula (3) can be prepared by treating compounds of formula (1) with a cold mixture of 1,3-dithiane and n-butyllithium, followed by a quench with citric acid, and then treatment with 4-toluenesulfonic acid.

Carboxylic acids of formula (3) can be coupled with sulfonamides of formula (4), wherein R³ is as described herein, to provide compounds of formula (5). Examples of conditions known to generate compounds of formula (5) from a mixture of a carboxylic acid and a sulfonamide include, but are not limited to, adding a coupling reagent such as, but not limited to, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC or EDCI) or the corresponding hydrochloride salt, 1,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide or 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HBTU), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®). The coupling reagents may be added as a solid, a solution, or as the reagent bound to a solid support resin. In addition to the coupling reagents, auxiliary-coupling reagents may facilitate the coupling reaction. Auxiliary coupling reagents that are often used in the coupling reactions include, but are not limited to, 4-(dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT) and 1-hydroxybenzotriazole (HOBT). The reaction may be carried out optionally in the presence of a base such as, but not limited to, triethylamine, N,N-diisopropylethylamine or pyridine. The coupling reaction may be carried out in solvents such as, but not limited to, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, and ethyl acetate. The reactions may be carried out at ambient temperature or an elevated temperature. The heating can be accomplished either conventionally or with microwave irradiation.

Alternatively, carboxylic acids of formula (3) can be treated with oxalyl chloride and a catalytic amount of N,N-dimethylformamide to provide compounds of formula (6). The reaction is typically performed in a solvent such as, but not limited to, dichloromethane, and may be performed at ambient or low temperature. Acid chlorides of formula (6) can be coupled with sulfonamides of formula (4), wherein R³ is as described herein, to provide compounds of formula (5). The reaction is typically performed in the presence of a base such as, but not limited to, triethylamine, and may be carried out in the presence of an auxiliary coupling reagents such as, but not limited to, 4-(dimethylamino)pyridine (DMAP).

Treatment of compounds of formula (5) with R¹X, wherein R¹ is as described herein and X is a halogen, and a base such as lithium bis(trimethylsilyl)amide, in a solvent system such as, but not limited to, tetrahydrofuran, and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, provides compounds of formula (7). The reaction is typically performed at low temperature before warming up to ambient temperature.

As shown in Scheme 2, compounds of formula (11) and (13), which are representative of compounds of Formula (I), can be prepared from compounds of formula (8). Compounds of formula (8) can be treated with 1-((isocyanomethyl)sulfonyl)-4-methylbenzene in the presence of a base such as potassium tert-butoxide, to provide compounds of formula (15). The reaction is typically performed at low temperature in a solvent such as, but not limited to, a mixture of dichloromethane and ethanol.

Alternatively, compounds of formula (8) can be treated with diethyl cyanophosphonate and LiCN to provide compounds of formula (14). The additions are typically performed at low temperature, such as 0° C., before warming up to ambient temperature, in a solvent such as, but not limited to, N,N-dimethylformamide. Compounds of formula (15) can be prepared by treating compounds of formula (14) with sodium borohydride. The reaction is typically performed at an elevated temperature in a solvent such as, but not limited to, ethanol.

Compounds of formula (15) can be treated with potassium hydroxide to provide compounds of formula (10). The reaction is typically performed at an elevated temperature in a solvent such as, but not limited to, a mixture of water and ethylene glycol.

Compounds of formula (9) can be prepared by treating compounds of formula (8) with a mixture of (methoxymethyl)triphenylphosphonium chloride and potassium tert-butoxide. The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran. Compounds of formula (9) can be treated with chromium trioxide in aqueous sulfuric acid to provide compounds of formula (10). The reaction is typically performed at low temperature in a solvent such as, but not limited to, acetone.

Carboxylic acids of formula (10) can be coupled with sulfonamides of formula (4), wherein R³ is as described herein, to provide compounds of formula (11), which are representative of compounds of Formula (I). Examples of conditions known to generate compounds of formula (11) from a mixture of a carboxylic acid and a sulfonamide include, but are not limited to, adding a coupling reagent such as, but not limited to, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC or EDCI) or the corresponding hydrochloride salt, 1,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide or 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HBTU), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®). The coupling reagents may be added as a solid, a solution, or as the reagent bound to a solid support resin. In addition to the coupling reagents, auxiliary-coupling reagents may facilitate the coupling reaction. Auxiliary coupling reagents that are often used in the coupling reactions include, but are not limited to, 4-(dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT) and 1-hydroxybenzotriazole (HOBT). The reaction may be carried out optionally in the presence of a base such as, but not limited to, triethylamine, N,N-diisopropylethylamine or pyridine. The coupling reaction may be carried out in solvents such as, but not limited to, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, and ethyl acetate. The reactions may be carried out at ambient temperature or an elevated temperature. The heating can be accomplished either conventionally or with microwave irradiation.

Treatment of compounds of formula (15) with sodium hydroxide provides compounds of formula (16). The reaction is typically performed at an elevated temperature in a solvent such as, but not limited to, ethanol. Compounds of formula (16) can be treated with sodium hydride and then reacted with compounds of formula (17), wherein R³ is as described herein, to provide compounds of formula (11), which are representative of compounds of Formula (I). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran.

Compounds of formula (10) can be treated with sulfuryl chloride to provide compounds of formula (12), wherein Y is Cl. The reaction is typically performed at low temperature, such as 0° C., and in a solvent such as, but not limited to, dichloromethane.

Carboxylic acids of formula (12) can be coupled with sulfonamides of formula (4), wherein R³ is as described herein, under conditions described for the preparation of compounds of formula (11) from compounds of formula (10), to provide compounds of formula (13), which are representative of compounds of Formula (I).

Compounds of formula (29), which are representative of compounds of Formula (I), can be prepared as described in Scheme 3. Compounds of formula (18), wherein X¹, X², X³, X⁴ are as described herein, can be treated with a prepared solution of tetrahydrofuran and n-butyllithium followed by lithium tetramethylpiperidine, to provide compounds of formula (19). The reaction is typically performed in tetrahydrofuran at low temperature, such as −78° C. Compounds of formula (20) can be treated with a prepared mixture of oxalyl chloride and dimethyl sulfoxide, followed by triethylamine, to provide compounds of formula (20). The reaction is typically performed in a solvent such as, but not limited to, dichloromethane, at a low temperature, such as −78° C. Compounds of formula (21) can be prepared by reacting a mixture of (methoxymethyl)triphenylphosphonium chloride and potassium tert-butoxide with compounds of formula (20). The reaction is typically performed at ambient temperature under a N₂ atmosphere in a solvent such as, but not limited to, tetrahydrofuran. Aldehydes of formula (23) can be prepared by reacting compounds of formula (21) with aqueous HCl. The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran. Treatment of compounds of formula (23) with CrO₃ in aqueous H₂SO₄ can provide compounds of formula (24). The reaction is typically performed at low temperature, such as 0° C., in a solvent such as, but not limited to, acetone, before being quenched with 2-propanol. Compounds of formula (24) can be reacted with, for example, ethanol in a strong base such as, but not limited to, H₂SO₄, to provide compounds of formula (25), wherein R^(x) CH₂CH₃. Compounds of formula (26), wherein Y is a halogen, can be prepared by reacting compounds of formula (25) under various conditions, for example, treatment with N-bromosuccinimide at low temperature in a solvent such as, but not limited to, acetonitrile to provide compounds of formula (26), wherein Y is Br.

Compounds of formula (26) can be reacted with boronic acids of formula (10A) (or the boronic ester equivalent) or zinc halides of formula (11A) wherein R⁸ is as described herein and X is I, Br, Cl or triflate, to provide compounds of formula (27). For example, compounds of formula (27) can be prepared by reacting compounds of formula (26) wherein Y is I, Br, Cl or triflate with boronic acid compounds of formula (10A), wherein R⁸ is as described herein (or the boronic ester equivalents), under Suzuki coupling conditions known to those skilled in the art and widely available in the literature. The reaction typically requires the use of a base and a catalyst. Examples of bases include, but are not limited to, potassium carbonate, potassium t-butoxide, sodium carbonate, cesium carbonate, and cesium fluoride. Examples of catalysts include, but are not limited to, tetrakis(triphenylphosphine)palladium(0), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane, bis(triphenylphosphine)palladium(II) dichloride, and tris(dibenzylideneacetone)dipalladium(0). The reaction may be conducted in a solvent such as, but not limited to, water, dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol, tetrahydrofuran and the like or mixtures thereof. The reaction may be conducted at ambient or elevated temperatures, and optionally in a microwave oven. Compounds of formula (27) can also be prepared by reacting compounds of formula (26) wherein X is I, Br, Cl or triflate with organozinc compounds of formula (11A), wherein R⁸ is as described herein, under Negishi coupling conditions known to those skilled in the art and widely available in the literature. The reaction typically requires the use of a palladium or nickel catalyst. Examples of catalysts include, but are not limited to, dichloro[4,5-dichloro-1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (PEPPSI-IPentCl), tetrakis(triphenylphosphine)nickel(0), tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane, tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate. The reaction may be conducted in a solvent such as, but not limited to, water, dioxane, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, 1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol, tetrahydrofuran and the like, or mixtures thereof. The reaction may be conducted at ambient or elevated temperatures, and optionally in a microwave oven.

Compounds of formula (27) can be treated with aqueous sodium hydroxide to provide compounds of formula (28). The reaction may be conducted at ambient or elevated temperatures and in a solvent such as, but not limited to, tetrahydrofuran and methanol, or mixtures thereof.

Carboxylic acids of formula (28) can be coupled with sulfonamides of formula (4), wherein R³ is as described herein, under conditions described herein for the preparation of compounds of formula (11) from compounds of formula (10), to provide compounds of formula (29), which are representative of compounds of Formula (I).

Compounds of formula (29), which are representative of compounds of Formula (I), can be prepared as described in Scheme 4. Compounds of formula (19), which can be prepared as described in Scheme 3, can be treated with N-bromosuccinimide to provide compounds of formula (30). The reaction is typically performed at ambient temperature, and in a solvent such as, but not limited to, acetonitrile. Compounds of formula (30) can be treated with carbon tetrabromide and triphenylphosphine to provide compounds of formula (31). The reaction is typically performed at ambient temperature, and in a solvent such as, but not limited to, methyl tert-butyl ether. Compounds of formula (32) can be prepared by treating compounds of formula (31) with tetrabutylammonium cyanide. The reaction is typically performed at ambient temperature, and in a solvent such as, but not limited to, tetrahydrofuran.

Compounds of formula (33) can also be prepared by reacting compounds of formula (32) with organozinc compounds of formula (11A), wherein R⁸ is as described herein, under Negishi coupling conditions known to those skilled in the art and widely available in the literature. The reaction typically requires the use of a palladium or nickel catalyst. Examples of catalysts include, but are not limited to, dichloro[4,5-dichloro-1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (PEPPSI-IPentCl), tetrakis(triphenylphosphine)nickel(0), tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane, tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate. The reaction may be conducted in a solvent such as, but not limited to, water, dioxane, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, 1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol, tetrahydrofuran and the like, or mixtures thereof. The reaction may be conducted at ambient or elevated temperatures, and optionally in a microwave oven.

Compounds of formula (33) can be treated with aqueous sodium hydroxide to provide compounds of formula (28). The reaction may be conducted at ambient or elevated temperatures and in a solvent such as, but not limited to, ethanol, tetrahydrofuran and methanol, or mixtures thereof.

Carboxylic acids of formula (28) can be coupled with sulfonamides of formula (4), wherein R³ is as described herein, under conditions described for the preparation of compounds of formula (11) from compounds of formula (10), to provide compounds of formula (29), which are representative of compounds of Formula (I).

EXAMPLES Example I-1 4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

The title compound was prepared and purified as described in Example I-6, substituting 4-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid for (R)-4-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.71-8.64 (m, 1H), 8.31-8.23 (m, 2H), 8.12 (d, J=8.3 Hz, 1H), 7.88-7.79 (m, 1H), 7.78-7.63 (m, 2H), 6.89 (t, J=7.9 Hz, 1H), 6.70 (d, J=8.2 Hz, 1H), 6.56 (d, J=7.5 Hz, 1H), 3.98 (dd, J=8.5, 5.7 Hz, 1H), 3.69 (s, 3H), 2.67 (h, J=9.3 Hz, 2H), 2.18-2.05 (m, 1H), 2.03-1.92 (m, 1H). MS (APCI+) m/z 381.9 (M+H)⁺.

Example I-2 8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Example I-2A 8-chloro-1,2,3,4-tetrahydronaphthalene-1-carbonitrile

Into a 20 mL vial containing a solution of 8-chloro-3,4-dihydronaphthalen-1(2H)-one (0.196 g, 1.085 mmol) (CAS#68449-32-1, purchased from AK) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (0.328 g, 1.682 mmol) in dichloromethane (5 mL) at −78° C. was added a solution of potassium 2-methylpropan-2-olate (2.007 mL, 2.007 mmol) and ethanol (0.070 g, 1.519 mmol). The reaction was allowed to warm to room temperature, was stirred for 16 hours, and quenched with aqueous HCl (0.5 M, 5 mL). The organic layer was separated and concentrated. The residue was chromatographed using a 25 g silica gel cartridge with a gradient of 5-50% ethyl acetate/hexanes over 20 minutes to give 8-chloro-1,2,3,4-tetrahydronaphthalene-1-carbonitrile. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.31-7.25 (m, 1H), 7.20 (t, J=7.8 Hz, 1H), 7.08 (dd, J=7.6, 1.2 Hz, 1H), 4.20 (dd, J=5.2, 2.4 Hz, 1H), 2.99-2.89 (m, 1H), 2.87-2.80 (m, 1H), 2.47-2.33 (m, 1H), 2.04 (tdq, J=10.4, 4.8, 2.5 Hz, 2H), 1.95-1.83 (m, 1H).

Example I-2B 8-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-2A (0.447 g, 2.332 mmol) was dissolved in ethanol (7.77 mL). A solution of 3.0 M aqueous sodium hydroxide (7.77 mL, 23.32 mmol) was added, and the resulting mixture was heated at 80° C. for 16 hours. The reaction was cooled in an ice bath and was acidified with 6 M aqueous HCl (5 mL). The resulting precipitate was filtered and washed with water to give 8-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxamide. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.26 (d, J=7.2 Hz, 1H), 7.17 (t, J=7.7 Hz, 1H), 7.09 (dd, J=7.7, 1.2 Hz, 1H), 5.49 (s, 1H), 5.25 (s, 1H), 3.95 (dd, J=6.2, 2.8 Hz, 1H), 2.90 (dt, J=17.2, 4.6 Hz, 1H), 2.86-2.75 (m, 1H), 2.42 (dddd, J=12.6, 7.3, 3.9, 2.5 Hz, 1H), 1.97-1.78 (m, 3H). MS (ESI+) m/z 210 (M+H⁺).

Example I-2C 8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-2B (50 mg, 0.238 mmol) was dissolved in tetrahydrofuran (2 mL) and sodium hydride (19.08 mg, 0.477 mmol) was added in portions. After stirring at room temperature for one hour, naphthalene-1-sulfonyl chloride (108 mg, 0.477 mmol) was added. After 30 minutes, the solvent was reduced in volume and the reaction was quenched with 0.5 mL of 1 N aqueous HCl. The organics were purified using a 12 g silica gel cartridge with an ethyl acetate/hexane solvent system to give 8-chloro-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.57-8.49 (m, 1H), 8.47-8.38 (m, 1H), 8.14 (d, J=8.2 Hz, 1H), 8.11-8.02 (m, 1H), 8.02-7.92 (m, 1H), 7.69-7.56 (m, 3H), 7.17 (t, J=7.7 Hz, 1H), 7.09 (dd, J=14.2, 7.7 Hz, 2H), 3.80 (dd, J=6.6, 3.3 Hz, 1H), 2.72 (dddd, J=23.1, 17.1, 11.0, 5.5 Hz, 2H), 2.23-2.11 (m, 1H), 1.85 (ddq, J=15.7, 10.0, 3.4 Hz, 1H), 1.73-1.58 (m, 1H), 1.52 (dd, J=8.5, 1.0 Hz, 1H). MS (APCI+) m/z 400 (M+H⁺).

Example I-3 (1R)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Example I-3A (R)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonyl chloride

To a solution of (R)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (58 mg, 0.281 mmol) in dichloromethane (2 mL) was added two drops of N,N-dimethylformamide followed by oxalyl dichloride (0.422 mL, 0.844 mmol). The reaction bubbled, and was stirred at ambient temperature for 1 hour. The solvent was removed under a stream of nitrogen and the resulting material was azeotroped with 1 mL of dichloromethane, and put under high vacuum for 5 minutes. The resulting (R)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonyl chloride was used directly in the next step.

Example I-3B (1R)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Naphthalene-1-sulfonamide (59 mg, 0.285 mmol) was dissolved in pyridine (0.5 mL) and cooled in an ice bath. A solution of Example I-3A (63 mg, 0.280 mmol) in 1 mL of dichloromethane was added dropwise over 5 minutes. The reaction was allowed to warm to room temperature. After 1 hour, the solvent was reduced under a stream of nitrogen. The reaction was quenched with 1 mL of 1 N aqueous HCl and dichloromethane. The organics were purified using a 10 g silica gel cartridge with an ethyl acetate/hexanes solvent system to give the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.53 (dd, J=7.5, 1.2 Hz, 1H), 8.29-8.20 (m, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.01-7.92 (m, 1H), 7.63 (td, J=7.1, 6.5, 3.9 Hz, 3H), 7.13 (t, J=7.9 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.46 (d, J=7.6 Hz, 1H), 3.90 (s, 3H), 3.88-3.79 (m, 1H), 3.56 (t, J=5.2 Hz, 1H), 2.62 (dt, J=18.0, 5.3 Hz, 1H), 2.56-2.43 (m, 1H), 2.02 (d, J=7.9 Hz, 1H), 1.85-1.69 (m, 1H), 1.66-1.55 (m, 1H). MS (APCI+) m/z 396 (M+H⁺).

Example I-4 5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

To a solution of 5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.494 g, 2.407 mmol) in tetrahydrofuran (6.02 mL) and N,N-dimethylformamide (6.02 mL) was added sodium hydride (0.193 g, 4.81 mmol) in portions. After stirring at room temperature for one hour, naphthalene-1-sulfonyl chloride (0.553 g, 2.440 mmol) was added in portions. After 1 hour, additional naphthalene-1-sulfonyl chloride (0.553 g, 2.440 mmol) was added and the reaction was stirred at room temperature for 16 hours. The solvent was reduced in vacuo. The reaction was quenched with 6 mL of 1 N aqueous HCl and water (10 mL) and stirred until cool. Crude material separated and was purified using a 10 g silica gel cartridge with an ethyl acetate/hexane solvent system to give 5-methoxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.53 (dd, J=7.5, 1.3 Hz, 1H), 8.28-8.18 (m, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.03-7.96 (m, 1H), 7.98 (s, 1H), 7.70-7.57 (m, 3H), 7.14 (t, J=7.9 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.46 (d, J=7.7 Hz, 1H), 3.90 (s, 3H), 3.56 (t, J=5.2 Hz, 1H), 2.62 (dt, J=18.7, 5.2 Hz, 1H), 2.49 (ddd, J=17.4, 9.5, 6.5 Hz, 1H), 2.11-1.98 (m, 1H), 1.85-1.70 (m, 1H), 1.67-1.55 (m, 1H), 1.38-1.23 (m, 1H). MS (APCI+) m/z 396 (M+H⁺).

Example I-5 1-benzyl-4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-8B (58 mg, <0.15 mmol) was dissolved into anhydrous N,N-dimethylimidazolinone (50 μL) and anhydrous tetrahydrofuran (250 μL), treated with benzyl bromide (19 μL, 0.16 mmol) and cooled below −15° C. with a dry ice/brine bath. Over 15 minutes, a solution of 1 M LiHMDS (lithium bis(trimethylsilyl)amide) in tetrahydrofuran (320 μL, 0.32 mmol) was added dropwise to the reaction mixture. The reaction mixture was kept ≤−15° C. for 40 minutes before being allowed to warm to 10° C. over two hours. The bath was removed and the reaction mixture was stirred at room temperature for 16 hours. Additional 1 M LiHMDS (lithium bis(trimethylsilyl)amide) in tetrahydrofuran (80 μL, 0.08 mmol) was added and the reaction mixture was stirred at room temperature for 70 minutes before additional benzyl bromide (9 μL, 0.08 mmol) was added followed by additional 1 M LiHMDS (lithium bis(trimethylsilyl)amide) in tetrahydrofuran (80 μL, 0.08 mmol). After another 90 minutes, the reaction was quenched with 1 M aqueous citric acid (300 μL) and was diluted with brine. The aqueous phase was separated and was extracted with methyl tert-butyl ether. The combined organic phases were dried (Na₂SO₄), filtered, concentrated and chromatographed on silica prepped with 1% acetic acid in 4:1 CHCl₃/heptane (80 to 100% CHCl₃/heptane). The crude product was suspended into 2:1 methyl tert-butyl ether/heptane and was collected by filtration. The collection vial was replaced and the material was rinsed through with dichloromethane. The second fraction was concentrated to give the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.33 (bs, 1H), 8.63 (d, J=7.9 Hz, 1H), 8.34-8.28 (m, 2H), 8.16-8.11 (m, 1H), 7.75-7.64 (m, 3H), 7.22 (d, J=7.9 Hz, 1H), 7.14-7.08 (m, 1H), 7.07-7.01 (m, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.91-6.84 (m, 2H), 6.62 (d, J=7.4 Hz, 2H), 3.23 (d, J=13.6 Hz, 1H), 2.94 (d, J=13.6 Hz, 1H), 2.65-2.55 (m, 1H), 2.28-2.12 (m, 3H). MS (ESI+) m/z 476 (M+H)⁺.

Example I-6 (1R)-4-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was added (R)-4-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (11 mg, 0.053 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (20.45 mg, 0.107 mmol), and N,N-dimethylpyridin-4-amine (7.17 mg, 0.059 mmol) in dichloromethane (0.5 mL). Naphthalene-1-sulfonamide (11.05 mg, 0.053 mmol) was added neat and the reaction was stirred for 16 hours at room temperature. The solvent was removed under a stream of nitrogen. The residue was reconstituted in acetonitrile and was purified using preparative reverse phase HPLC/MS method TFA8 to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.62-8.54 (m, 1H), 8.30-8.22 (m, 2H), 8.19-8.03 (m, 1H), 7.76-7.64 (m, 3H), 7.06 (t, J=7.8 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 6.61 (d, J=7.6 Hz, 1H), 3.74 (s, 3H), 2.74-2.55 (m, 2H), 2.42-2.30 (m, 1H), 1.85-1.73 (m, 1H), 1.27 (s, 3H). MS (APCI+) m/z 396.0 (M+H)⁺.

Example I-7 4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-8B (58 mg, <0.15 mmol) was dissolved into anhydrous N,N-dimethylimidazolinone (50 μL) and anhydrous tetrahydrofuran (250 μL), treated with iodoethane (27 μL, 0.34 mmol) and cooled to 0° C. A solution of 1 M LiHMDS (lithium bis(trimethylsilyl)amide) in tetrahydrofuran (450 μL, 0.45 mmol) was added dropwise and the reaction mixture was stirred cold five minutes before the bath was removed. Stirring was continued at room temperature for 16 hours. Additional iodoethane (9 μL, 0.11 mmol) was added followed by dropwise addition of 1 M LiHMDS in tetrahydrofuran (70 μL, 0.07 mmol). After the mixture had been stirred for 40 minutes, the reaction was quenched with 1 M aqueous citric acid (300 μL), concentrated, and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 90% gradient of acetonitrile in 0.1% aqueous TFA] to give the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.12 (bs, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.30-8.23 (m, 2H), 8.11-8.07 (m, 1H), 7.73-7.63 (m, 3H), 7.25-7.19 (m, 2H), 7.18-7.13 (m, 1H), 2.84-2.73 (m, 2H), 2.37-2.29 (m, 1H), 2.04-1.90 (m, 2H), 1.68-1.60 (m, 1H), 0.46 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 414 (M+H)⁺.

Example I-8 4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-8A 4-chloro-2,3-dihydro-1H-indene-1-carboxylic acid

A solution of 1,3-dithiane (7.58 g, 63.0 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen was cooled to −35° C. n-Butyllithium in hexanes (1.6 M, 39 mL, 62 mmol) was added portionwise over one hour, keeping the internal temperature below −25° C. during the entire addition. After 30 minutes near −25° C., the internal temperature was allowed to slowly rise to −5° C., over another hour. A solution of 4-chloroindanone (10.0 g, 60.0 mmol) in anhydrous tetrahydrofuran (270 mL) was added over 35 minutes, keeping the internal temperature below 0° C. during the entire addition. The reaction mixture was permitted to very slowly warm to room temperature over the weekend and was quenched with 3 M aqueous citric acid (7 mL) and was diluted with brine (20 mL). The resulting aqueous suspension was separated, and the aqueous phase was further extracted with methyl tert-butyl ether. The combined organic phases were washed with brine, dried (Na₂SO₄), filtered, and concentrated. The residue was dissolved into toluene (120 mL). 4-Toluenesulfonic acid hydrate (1.14 g, 6.0 mmol) was added, and the solution was refluxed for two hours with a Dean-Stark apparatus attached to the flask. The reaction mixture was cooled to near room temperature, washed twice with water, and each aqueous layer was back-extracted once with methyl tert-butyl ether. The combined organic phases were concentrated. The residue was dissolved in acetic acid (200 mL), treated with concentrated aqueous HCl (60 mL), and heated at 100° C. for three hours. The mixture was concentrated. The residue was dissolved in chloroform, dried (Na₂SO₄), filtered, and concentrated. Chloroform (20 mL) was added to the residue, and the mixture was treated slowly with heptane (30 mL). The resulting suspension was left standing for 16 hours. The material was collected by filtration, rinsed with 1:4 CHCl₃/heptane, and dried under vacuum. Three additional crops were obtained in a similar fashion to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.31 (d, J=7.5 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.14 (dd, J=7.9, 7.5 Hz, 1H), 4.14 (dd, J=8.7, 6.0 Hz, 1H), 3.15 (ddd, J=16.5, 8.8, 6.1 Hz, 1H), 2.97 (ddd, J=16.5, 8.8, 6.1 Hz, 1H), 2.47 (dddd, J=13.2, 8.8, 6.1, 6.0 Hz, 1H), 2.37 (dddd, J=13.2, 8.8, 8.7, 6.1 Hz, 1H). MS (DCI) m/z 214 (M⁺NH₄)⁺.

Example I-8B 4-chloro-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a suspension of Example I-8A (1.18 g, 6.0 mmol) and 1-hydroxy-7-azabenzotriazole (136 mg, 1.0 mmol) in anhydrous acetonitrile (10 mL) was added a suspension of carbonyl diimidazole (1.07 g, 6.6 mmol) in acetonitrile (10 mL) over four minutes. The resulting solution was stirred at room temperature for 30 minutes before napthalene-1-sulfonamide (1.37 g, 6.6 mmol) was added, and the reaction mixture was heated at 65° C. for 16 hours. The reaction mixture was cooled to near room temperature, acidified with trifluoroacetic acid (1.2 mL), and concentrated. The crude material was partitioned between water and methyl tert-butyl ether. The aqueous phase was separated and extracted with methyl tert-butyl ether. The combined organic phases were washed with brine, dried (Na₂SO₄), filtered, and concentrated. The residue was chromatographed on silica (30 to 65% methyl tert-butyl ether/heptane) to provide the crude title compound. The crude material was further purified by reverse-phase HPLC (Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 70% gradient of acetonitrile in 0.1% aqueous TFA). ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.84 (bs, 1H), 8.70-8.65 (m, 1H), 8.30-8.26 (m, 2H), 8.14-8.10 (m, 1H), 7.84 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.72 (ddd, J=8.1, 6.9, 1.1 Hz, 1H), 7.67 (dd, J=7.8, 7.8 Hz, 1H), 7.18-7.13 (m, 1H), 6.97-6.92 (m, 2H), 4.09 (dd, J=8.6, 5.7 Hz, 1H), 2.82-2.76 (m, 2H), 2.22-2.12 (m, 1H), 2.05-1.96 (m, 1H). MS (ESI+) m/z 386 (M+H)⁺.

Example I-9 1-benzyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-4 (20 mg, 50 μmol) was dissolved into a mixture of anhydrous N,N-dimethylimidazolinone (20 μL) and anhydrous tetrahydrofuran (100 μL), cooled to 0° C. and treated with 1 M LiHMDS (lithium bis(trimethylsilyl)amide)in tetrahydrofuran (100 μL, 0.10 mmol). After several minutes, benzyl bromide (12 μL, 0.10 mmol) was added dropwise, followed after several more minutes by dropwise addition of additional 1 M LiHMDS in tetrahydrofuran (50 μL, 0.05 mmol). The reaction mixture was stirred cold 20 minutes, then removed from the bath and stirred at room temperature for 16 hours. Additional 1 M LiHMDS in tetrahydrofuran (50 μL, 0.05 mmol) was added, followed by benzyl bromide (6 μL, 0.05 mmol). After the reaction mixture had been stirred for about two hours and again after another two hours, the same amounts of each reagent were added. After stirring for another two hours, the reaction was quenched with 1 M aqueous citric acid (150 μL), concentrated and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 90% gradient of acetonitrile in 0.1% aqueous TFA] to give the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.94 (bs, 1H), 8.52-8.47 (m, 1H), 8.34-8.29 (m, 2H), 8.15-8.10 (m, 1H), 7.75-7.69 (m, 1H), 7.69-7.58 (m, 2H), 7.41-7.36 (m, 1H), 7.30-7.24 (m, 1H), 7.05-7.00 (m, 1H), 6.99-6.93 (m, 1H), 6.92-6.86 (m, 1H), 6.78-6.71 (m, 2H), 6.40-6.35 (m, 1H), 3.75 (s, 3H), 3.21 (d, J=13.8 Hz, 1H), 2.92 (d, J=13.8 Hz, 1H), 2.43-2.36 (m, 2H), 2.05-1.96 (m, 1H), 1.47-1.20 (m, 3H). MS (ESI+) m/z 486 (M+H)⁺.

Example I-10 1-ethyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-4 (20 mg, 50 μmol) was dissolved into a mixture of anhydrous N,N-dimethylimidazolinone (20 μL) and anhydrous tetrahydrofuran (100 μL), cooled to 0° C. and treated with 1 M LiHMDS (lithium bis(trimethylsilyl)amide) in tetrahydrofuran (100 μL, 0.10 mmol). After several minutes, iodoethane (8.1 μL, 0.10 mmol) was added dropwise, followed after several more minutes by dropwise addition of more 1 M LiHMDS in tetrahydrofuran (50 μL, 0.05 mmol). The reaction mixture was stirred cold 20 minutes, then removed from the bath and stirred at room temperature for 16 hours. Additional 1 M LiHMDS in tetrahydrofuran (50 μL, 0.05 mmol) was added, followed by additional iodoethane (4 μL, 0.05 mmol). After the reaction mixture had been stirred for about two hours and again after another two hours, the same amounts of each reagent were added. After being stirred another two hours, the reaction was quenched with 1 M aqueous citric acid (150 μL), concentrated and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 80% gradient of acetonitrile in 0.1% aqueous TFA] to give the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.81 (bs, 1H), 8.53-8.49 (m, 1H), 8.31-8.26 (m, 2H), 8.13-8.09 (m, 1H), 7.72-7.61 (m, 3H), 6.90-6.85 (m, 1H), 6.77-6.74 (m, 1H), 6.25-6.21 (m, 1H), 3.74 (s, 3H), 2.55-2.40 (m, 2H), 2.08-1.99 (m, 1H), 1.88-1.77 (m, 1H), 1.61-1.50 (m, 2H), 1.50-1.38 (m, 2H), 0.57 (t, J=7.3 Hz, 3H). MS (ESI+) m/z=424 (M+H)⁺.

Example I-11 (1R)-8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-2 (125 mg) was separated by chiral preparative SFC chromatography using a CHIRALPAK OJ-H, column size 21×250 mm, 5 micron, serial Number: OJHSAMA003-810291, using a concentration of 12.4 mg/mL in methanol at a flow rate of 56 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. R_(T) (chiral SFC)=4.2 minutes. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.52 (dd, J=7.4, 1.3 Hz, 1H), 8.50-8.43 (m, 1H), 8.27 (s, 1H), 8.13 (dt, J=8.2, 1.0 Hz, 1H), 8.02-7.94 (m, 1H), 7.62 (dqd, J=11.3, 8.1, 7.5, 4.7 Hz, 3H), 7.18-7.11 (m, 1H), 7.05 (ddd, J=14.7, 7.7, 1.4 Hz, 2H), 3.80 (dd, J=6.6, 3.3 Hz, 1H), 2.70 (dddd, J=23.0, 16.9, 10.9, 5.4 Hz, 2H), 2.21-2.10 (m, 1H), 1.84 (dddd, J=13.7, 12.0, 6.6, 3.4 Hz, 1H), 1.69-1.43 (m, 2H). MS (APCI+) m/z 400 (M+H⁺).

Example I-12 (1S)-8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-2 (125 mg) was separated by chiral preparative SFC chromatography using a CHIRALPAK OJ-H, column size 21×250 mm, 5 micron, serial Number: OJHSAMA003-810291, using a concentration of 12.4 mg/mL in methanol at a flow rate of 56 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. R_(T) (chiral SFC)=3.3 min. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.52 (dd, J=7.4, 1.3 Hz, 1H), 8.47-8.42 (m, 1H), 8.22 (s, 1H), 8.15-8.11 (m, 1H), 8.01-7.95 (m, 1H), 7.70-7.58 (m, 3H), 7.15 (t, J=7.7 Hz, 1H), 7.07 (ddd, J=14.4, 7.7, 1.4 Hz, 2H), 3.80 (dd, J=6.7, 3.3 Hz, 1H), 2.71 (dddd, J=22.9, 16.8, 10.9, 5.3 Hz, 2H), 2.24-2.11 (m, 1H), 1.85 (dddd, J=13.7, 11.9, 6.6, 3.4 Hz, 1H), 1.72-1.44 (m, 2H). MS (APCI+) m/z 400 (M+H⁺). The absolute structure of the title compound was determined by X-ray crystallography.

Example I-13 4-chloro-N-(2,2-difluoro-2H-1,3-benzodioxole-4-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide

To a solution of Example I-17A (27 mg, 0.12 mmol) and PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 83 mg, 0.16 mmol) in anhydrous N,N-dimethylformamide (300 μL) at room temperature was added N,N-diisopropylethylamine (63 μL, 0.36 mmol) followed by 2,2-difluorobenzo[d][1,3]dioxole-4-sulfonamide (38 mg, 0.16 mmol [Enamine]). The solution was heated at 45° C. for 16 hours. The reaction mixture was brought to room temperature, diluted with methanol and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 80% gradient of acetonitrile in 0.1% aqueous TFA] to give the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 8.10 (bs, 1H), 7.72 (dd, J=8.2, 1.2 Hz, 1H), 7.34 (dd, J=8.1, 1.2 Hz, 1H), 7.30 (dd, J=7.9, 0.9 Hz, 1H), 7.27 (dd, J=8.2, 8.1 Hz, 1H), 7.25-7.21 (m, 1H), 7.10 (dd, J=7.5, 0.9 Hz, 1H), 3.05-2.94 (m, 2H), 2.47 (ddd, J=13.3, 8.5, 6.4 Hz, 1H), 2.12 (ddd, J=13.3, 8.3, 6.4 Hz, 1H), 1.93 (dq, J=14.2, 7.4 Hz, 2H), 1.86 (dq, J=14.2, 7.4 Hz, 1H), 0.75 (dd, J=7.4 Hz, 3H). MS (ESI+) m/z 444 (M+H)⁺.

Example I-14 7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was added 7-chloro-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (54 mg, 0.256 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (98 mg, 0.513 mmol), and N,N-dimethylpyridin-4-amine (34.4 mg, 0.282 mmol) in dichloromethane (0.5 mL). Naphthalene-1-sulfonamide (53.1 mg, 0.256 mmol) was added neat and the mixture was stirred at room temperature for 16 hours. The solvent was removed under a stream of nitrogen. The residue was reconstituted in acetonitrile and was purified using preparative reverse phase HPLC/MS method TFA8 to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.65-8.56 (m, 1H), 8.35-8.25 (m, 2H), 8.16-8.07 (m, 1H), 7.75-7.64 (m, 3H), 7.30-7.17 (m, 2H), 7.14-7.07 (m, 1H), 3.02-2.84 (m, 2H), 2.22 (dt, J=12.6, 9.4 Hz, 1H), 1.82-1.71 (m, 1H), 1.22 (s, 3H). MS (APCI+) m/z 400.0 (M+H)⁺.

Example I-15 8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Example I-15A 8-bromo-5-methoxy-3,4-dihydronaphthalene-1-carbonitrile

A flask containing 1.6 M n-butyllithium in hexanes (4.66 mL, 7.46 mmol) was cooled to −78° C. under N₂ and was treated dropwise with a solution of trimethylsilyl cyanide (1 mL, 7.46 mmol) in tetrahydrofuran (5 mL). The mixture was warmed to room temperature and was stirred for 1 hour. The mixture was diluted with heptanes (50 mL) and the material was collected by filtration to provide material which contained LiCN. In a separate flask, a solution of 8-bromo-5-methoxy-3,4-dihydronaphthalen-1(2H)-one (CAS#3693944-3, 2.8 g, 10.98 mmol) in N,N-dimethylformamide (10 mL) was cooled to 0° C., treated with diethyl cyanophosphonate (3.33 mL, 21.95 mmol), and treated with 190 mg of the prepared LiCN containing material. The mixture was stirred at room temperature for 2 hours and was partitioned between methyl tert-butyl ether (˜100 mL) and water (˜50 mL). The aqueous layer was extracted with methyl tert-butyl ether (2×30 mL). The combined methyl tert-butyl ether layers were washed with water (25 mL), washed with brine (10 mL), dried (MgSO₄), filtered, and concentrated. The residue was dissolved in toluene (100 mL), treated with p-toluenesulfonic acid monohydrate (0.209 g, 1.098 mmol), and heated to reflux for 3 hours. The mixture was cooled, diluted with methyl tert-butyl ether (˜100 mL), washed with aqueous NaHCO₃ solution (˜50 mL), washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was chromatographed on silica gel, eluting with a gradient of 20% to 50% dichloromethane in heptanes to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.44 (d, J=8.9 Hz, 1H), 7.19 (t, J=5.3 Hz, 1H), 6.75 (d, J=8.9 Hz, 1H), 3.83 (s, 3H), 2.81-2.77 (m, 2H), 2.36-2.30 (m, 2H).

Example I-15B 8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile

A solution of Example I-15A (2.47 g, 9.35 mmol) in ethanol (75 mL) was treated with NaBH₄ (2.123 g, 56.1 mmol), and the mixture was heated to reflux for 25 minutes. The mixture was concentrated to dryness. The residue was treated with saturated aqueous NaHCO₃ solution (100 mL) and methyl tert-butyl ether (150 mL), and stirred for 15 minutes. The layers were separated, and the aqueous layer was extracted with methyl tert-butyl ether (75 mL). The combined methyl tert-butyl ether layers were washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was chromatographed on silica gel, eluting with a gradient of 5% to 15% ethyl acetate in heptanes to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.41 (d, J=8.7 Hz, 1H), 6.69 (d, J=8.7 Hz, 1H), 4.13 (d, J=4.3 Hz, 1H), 3.81 (s, 3H), 2.93 (dd, J=18.3, 5.4 Hz, 1H), 2.47 (ddd, J=18.4, 11.8, 6.7 Hz, 1H), 2.36-2.29 (m, 1H), 2.10-2.02 (m, 1H), 1.94 (qdd, J=13.5, 5.5, 2.2 Hz, 1H), 1.81 (tdd, J=13.3, 4.9, 2.7 Hz, 1H).

Example I-15C 8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide

A solution of Example I-15B (1.68 g, 6.31 mmol) in ethanol (20 mL) was treated with 3 M aqueous NaOH (21.04 mL, 63.1 mmol), and the mixture was heated to 80° C. 16 hours. The mixture was cooled to 0° C., treated with water (100 mL), and stirred at 0° C. for 15 minutes. The material was collected by filtration, washed with water, and dried under vacuum for 1 hour at 50° C. to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 7.35 (d, J=8.7 Hz, 1H), 7.27 (bs, 1H), 6.88 (bs, 1H), 6.78 (d, J=8.8 Hz, 1H), 3.77 (s, 3H), 3.74-3.71 (m, 1H), 2.70 (dd, J=17.9, 4.2 Hz, 1H), 2.39 (ddd, J=17.7, 11.1, 6.4 Hz, 1H), 2.12-2.01 (m, 1H), 1.80-1.55 (m, 3H). LC/MS (APCI+) m/z 284,286 (M+H)⁺.

Example I-15D 8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

A solution of Example I-15C (1.51 g, 5.31 mmol) in tetrahydrofuran (50 mL) under N₂ was treated with 60% dispersion of sodium hydride in mineral oil (0.468 g, 11.69 mmol), stirred at room temperature for 1 hour, and cooled to 0° C. The mixture was treated dropwise with a solution of 1-naphthalenesulfonyl chloride (1.325 g, 5.85 mmol) in tetrahydrofuran (20 mL), stirred at room temperature for 1 hour, and heated to reflux for 16 hours. The mixture was cooled and concentrated to remove the majority of the tetrahydrofuran. The mixture was treated with methyl tert-butyl ether (˜20 mL) and 1 M aqueous HCl (15 mL), and then treated with additional methyl tert-butyl ether (˜100 mL). The layers were separated, and the organic layer was washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was treated with methyl tert-butyl ether (˜15 mL) and stirred. Material began to precipitate, and heptanes (30-50 mL) were slowly added. The material was collected by filtration, washed with cold 5:1 heptanes:methyl tert-butyl ether, and dried under vacuum with heating at 50° C. for 30 minutes to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.71 (s, 1H), 8.69 (d, J=8.6 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.24 (dd, J=7.4, 0.9 Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.76 (ddd, J=8.4, 6.9, 1.2 Hz, 1H), 7.70-7.63 (m, 2H), 7.13 (d, J=8.7 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 3.78 (dd, J=6.9, 2.8 Hz, 1H), 3.69 (s, 3H), 2.55-2.47 (m, 1H), 2.25 (ddd, J=17.7, 11.3, 6.2 Hz, 1H), 1.95-1.88 (m, 1H), 1.74 (dddd, J=13.4, 8.8, 6.4, 3.2 Hz, 1H), 1.50-1.42 (m, 1H), 1.09-0.97 (m, 1H). LC/MS (APCI+) m/z 474, 476 (M+H)⁺.

Example I-16 4-chloro-1-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-16A 4-chloro-1-(2,2-dimethoxyethyl)-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-8B (386 mg, 1.0 mmol) was placed under nitrogen, dissolved into anhydrous DMI (1,3-dimethyl-2-imidazolidinone) (300 μL) and anhydrous tetrahydrofuran (1.2 mL), cooled to 0° C. and treated with 1 M LiHMDS (lithium bis(trimethylsilyl)amide) in tetrahydrofuran (2.0 mL, 2 mmol). 2-Bromo-1,1-dimethoxyethane (235 μL, 2.0 mmol) was added dropwise over eight minutes and after twelve more minutes the cold bath was removed. The solution was stirred at room temperature for three days and then additional 1 M LiHMDS in tetrahydrofuran (1.0 mL, 1 mmol) was added dropwise followed by more 2-bromo-1,1-dimethoxyethane (120 μL, 1.0 mmol). The reaction mixture was stirred at room temperature for 24 hours more and was quenched with 1 M aqueous citric acid (1 mL) and diluted with brine (1 mL). The aqueous phase was separated and was extracted with methyl tert-butyl ether. The combined organic phases were dried (Na₂SO₄), filtered, and concentrated. The residue was diluted with dilute brine and extracted with ethyl acetate/methyl tert-butyl ether. The combined organic phases were washed with dilute brine and then with brine, dried (Na₂SO₄), filtered, and concentrated. The residue was mixed with silica gel, dichloromethane and heptane and placed atop a silica column for chromatography (50 to 80% methyl tert-butyl ether/heptane) to give the crude title compound. ¹H NMR (501 MHz, CD₂Cl₂) δ ppm 9.32 (bs, 1H), 8.46-8.42 (m, 2H), 8.17-8.15 (m, 1H), 8.02-7.99 (m, 1H), 7.70-7.60 (m, 3H), 7.22 (dd, J=8.0, 0.9 Hz, 1H), 7.08-7.04 (m, 1H), 6.91-6.88 (m, 1H), 4.08 (t, J=5.6 Hz, 1H), 3.13 (s, 3H), 3.11 (s, 3H), 2.89-2.80 (m, 2H), 2.37 (ddd, J=13.2, 8.4, 6.9 Hz, 1H), 2.09-2.02 (m, 3H). MS (ESI−) m/z 472 (M−H)⁻.

Example I-16B 4-chloro-1-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-16A (29 mg, ≤60 μmol) was dissolved into tetrahydrofuran (300 μL), treated with two drops of 2 M aqueous HCl, stirred at room temperature for 20 minutes and concentrated. The residue was dissolved into buffer (300 μL) (prepared from 3.6 g sodium acetate trihydrate, 4.6 mL acetic acid and sufficient methanol to bring the total volume to 100 mL) with 3,3-difluoropyrrolidine hydrochloride (12 mg, 84 μmol), and treated with sodium cyanoborohydride (6 mg, 95 μmol) and stirred at room temperature for 16 hours. The reaction mixture was diluted with N,N-dimethylformamide and methanol and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-70% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound. ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 8.70-8.66 (m, 1H), 8.41-8.38 (m, 1H), 8.09 (d, J=8.2 Hz, 1H), 8.01-7.97 (m, 1H), 7.76-7.71 (m, 1H), 7.68-7.62 (m, 1H), 7.58-7.53 (m, 1H), 7.12-7.08 (m, 1H), 6.86-6.81 (m, 1H), 6.62 (d, J=7.6 Hz, 1H), 3.32-2.99 (m, 4H), 2.82-2.76 (m, 2H), 2.68-2.47 (m, 5H), 1.94-1.83 (m, 3H). MS (ESI+) m/z=519 (M+H)⁺.

Example I-17 (1S)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-17A 4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxylic acid

A solution of 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (12.71 mL, 12.71 mmol) was cooled to 0° C. under N₂, treated dropwise with a solution of 4-chloro-2,3-dihydro-1H-indene-1-carboxylic acid (1 g, 5.09 mmol) in tetrahydrofuran (10 mL), and stirred at 0° C. for 15 minutes. The mixture was treated portionwise over 10 minutes with ethyl iodide (0.658 mL, 8.14 mmol), stirred at room temperature for 15 minutes, heated to 50° C. for 75 minutes, cooled, and treated with 3 M aqueous NaOH (3.39 mL, 10.17 mmol). The mixture was stirred for 1 hour, concentrated to remove most of the tetrahydrofuran, and partitioned between methyl tert-butyl ether (100 mL) and 1 M aqueous HCl (40 mL). The layers were separated, and the aqueous layer was extracted with methyl tert-butyl ether (2×30 mL). The combined methyl tert-butyl ether layers were washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was chromatographed on silica gel, eluting with a gradient of 20 to 50% 200:1:1 ethyl acetate:HCOOH:H₂O in heptanes to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.28 (d, J=7.5 Hz, 1H), 7.23-7.20 (m, 1H), 7.15 (t, J=7.7 Hz, 1H), 3.07 (dt, J=16.1, 8.0 Hz, 1H), 2.96 (ddd, J=16.6, 8.9, 4.6 Hz, 1H), 2.72 (ddd, J=13.2, 8.7, 4.6 Hz, 1H), 2.20 (dq, J=14.7, 7.4 Hz, 1H), 2.01 (ddd, J=13.2, 8.8, 7.4 Hz, 1H), 1.76 (dq, J=14.8, 7.4 Hz, 1H), 0.92 (t, J=7.4 Hz, 3H).

Example I-17B (S)-4-chloro-1-ethyl-N—((S)-2-hydroxy-1-phenylethyl)-2,3-dihydro-1H-indene-1-carboxamide

A solution of Example I-17A (0.29 g, 1.291 mmol) in dichloromethane (5 mL) was cooled to 0° C., and treated all at once with oxalyl chloride (0.565 mL, 6.45 mmol). The mixture was treated with 1 drop of N,N-dimethylformamide, stirred at room temperature for 45 minutes, and concentrated. The residue was dissolved in dichloromethane (˜2 mL) and added dropwise to a 0° C. solution of (S)-(+)-2-phenylglycinol (0.266 g, 1.936 mmol) and triethylamine (0.360 mL, 2.58 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature for 30 minutes and was concentrated. The residue was partitioned between ethyl acetate (50 mL) and 1 M aqueous HCl (˜25 mL). The material that was present between the layers was isolated by filtration. The material was determined to be a mixture of the desired products. The layers of the filtrate were separated, and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined ethyl acetate layers were washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was combined with the material isolated by filtration and was dissolved in dichloromethane (75 mL). Silica gel (3 g) was added, and the mixture was concentrated to dryness. The silica gel suspension of the crude product was purified by silica gel chromatography, eluting with a gradient of 25 to 100% methyl tert-butyl ether in heptanes to provide the title compound as the first diastereomer to elute from the column. ¹H NMR (501 MHz, CDCl₃) δ ppm 7.42-7.31 (m, 4H), 7.29-7.21 (m, 4H), 6.27 (d, J=6.8 Hz, 1H), 5.13-5.09 (m, 1H), 3.88-3.80 (m, 2H), 3.14-3.03 (m, 2H), 2.65 (ddd, J=13.7, 8.1, 5.7 Hz, 1H), 2.41 (t, J=6.0 Hz, 1H), 2.25 (ddd, J=13.2, 8.3, 7.3 Hz, 1H), 2.12 (dq, J=14.8, 7.4 Hz, 1H), 2.01 (dq, J=14.7, 7.4 Hz, 1H), 0.92 (t, J=7.4 Hz, 3H). LC/MS (APCI+) m/z 344 (M+H)⁺.

Example I-17C (S)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxylic acid

A solution of Example I-17B (200 mg, 0.582 mmol) in ethylene glycol (4 mL) was treated with 4 mL of a 10% w/v KOH solution in water (3916 mg, 6.98 mmol), heated to 130° C. for 6 hours, cooled, and partitioned between methyl tert-butyl ether (25 mL) and water (25 mL). The methyl tert-butyl ether layer was discarded. The aqueous layer was acidified with 6 M aqueous HCl and was extracted with methyl tert-butyl ether. The organic layer was washed with 0.1 M aqueous HCl (25 mL), washed with brine, dried (MgSO₄), filtered, and concentrated to provide the title compound.

Example I-17D (1S)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of Example I-17C (95 mg, 0.42 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (161 mg, 0.84 mmol) and 4-dimethylaminopyridine (56 mg, 0.46 mmol) in anhydrous dichloromethane (1.0 mL) was added naphthalene-1-sulfonamide (95 mg, 0.46 mmol). The mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated and purified by reverse-phase HPLC (Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 100% gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid) to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.11 (bs, 1H), 8.59 (d, J=8.3 Hz, 1H), 8.30-8.26 (m, 2H), 8.12-8.08 (m, 1H), 7.73-7.64 (m, 3H), 7.25-7.19 (m, 2H), 7.17-7.12 (m, 1H), 2.84-2.68 (m, 2H), 2.31 (ddd, J=13.0, 8.5, 6.3 Hz, 1H), 2.06-1.91 (m, 2H), 1.65 (dq, J=14.6, 7.3 Hz, 1H), 0.45 (t, J=7.3 Hz, 3H). MS (ESI+) m/z=414 (M+H)⁺.

Example I-18 (1R)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-18A (R)-4-chloro-1-ethyl-N—((S)-2-hydroxy-1-phenylethyl)-2,3-dihydro-1H-indene-1-carboxamide

The title compound was prepared as described in Example I-17B, and was isolated as the second diastereomer to elute from the column. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.33-7.20 (m, 6H), 7.12-7.08 (m, 2H), 6.23 (d, J=6.7 Hz, 1H), 5.04-5.00 (m, 1H), 3.88-3.74 (m, 2H), 2.97 (t, J=7.3 Hz, 2H), 2.57-2.47 (m, 2H), 2.15 (dt, J=13.2, 7.7 Hz, 1H), 2.02 (dtt, J=21.3, 14.4, 7.4 Hz, 2H), 0.89 (t, J=7.4 Hz, 3H). LC/MS (APCI+) m/z 344 (M+H)⁺.

Example I-18B (R)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxylic acid

A solution of (R)-4-chloro-1-ethyl-N—((S)-2-hydroxy-1-phenylethyl)-2,3-dihydro-1H-indene-1-carboxamide (200 mg, 0.582 mmol) in ethylene glycol (4 mL) was treated with 4 mL of a 10% w/v KOH solution in water (3916 mg, 6.98 mmol). The mixture was heated to 130° C. for 3 hours, cooled, and partitioned between methyl tert-butyl ether (25 mL) and water (25 mL). The methyl tert-butyl ether layer was discarded. The aqueous layer was acidified with 6 M aqueous HCl and extracted with methyl tert-butyl ether. The organic layer was washed with 0.1 M aqueous HCl (25 mL), washed with brine, dried (MgSO₄), filtered, and concentrated to provide the title compound.

Example I-18C (1R)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of Example I-18B (95 mg, 0.42 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (161 mg, 0.84 mmol) and 4-dimethylaminopyridine (56 mg, 0.46 mmol) in anhydrous dichloromethane (1.0 mL) was added naphthalene-1-sulfonamide (95 mg, 0.46 mmol). The mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated and purified by reverse-phase HPLC (Waters XBridge™ C18 5 urn OBD column, 30×100 mm, flow rate 40 mL/minute, 20% to 100% gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid) to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.11 (bs, 1H), 8.59 (d, J=8.3 Hz, 1H), 8.30-8.26 (m, 2H), 8.11-8.08 (m, 1H), 7.73-7.64 (m, 3H), 7.25-7.19 (m, 2H), 7.17-7.12 (m, 1H), 2.84-2.68 (m, 2H), 2.31 (ddd, J=13.0, 8.5, 6.3 Hz, 1H), 2.05-1.91 (m, 2H), 1.65 (dq, J=14.5, 7.3 Hz, 1H), 0.45 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 414 (M+H)⁺.

Example I-19 4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-19A 4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonitrile

In a 50 mL round bottom flask, 4-bromo-7-methoxy-2,3-dihydro-1H-inden-1-one (0.977 g, 4.05 mmol) (CAS#5411-61-0, Aldrich) and TOSMIC (toluenesulfonylmethyl isocyanide, 1.029 g, 5.27 mmol) were dissolved in dimethoxyethane (20 mL). The reaction was cooled under nitrogen to −8° C. with an ice/acetone/dry ice bath. Solid potassium tert-butoxide (1.046 g, 9.32 mmol) was added in portions keeping the internal temperature <−5° C. over about an hour. The reaction was allowed to slowly warm to room temperature for 16 hours. The solvent was removed in vacuo and the crude material was quenched with water (30 mL). The aqueous layer was extracted with ether (4×50 mL) and the organics were washed with brine, dried (Na₂SO₄), and filtered. The solvent was removed in vacuo and the crude material was chromatographed using a 40 g silica gel cartridge with 1-50% ethyl acetate/hexanes to give the title compound. ¹H NMR (400 MHz, Chloroform-d) δ 7.40 (dd, J=8.7, 0.7 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H ppm), 4.23-4.17 (m, 1H), 3.89 (s, 3H), 3.24-3.11 (m, 1H), 3.06-2.95 (m, 1H), 2.61-2.42 (m, 2H).

Example I-19B 4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid

Example I-19A (1.3 g, 5.16 mmol) was dissolved in ethanol (17.2 mL). A solution of sodium hydroxide (2.06 g, 51.6 mmol) in 17.2 mL of water was added, and the resulting mixture was heated at 80° C. for 16 hours. The reaction was cooled in an ice bath and was acidified with 6 M aqueous HCl (11 mL) to pH ˜2. The resulting precipitate was filtered and washed with water to give the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 7.38 (d, J=8.6 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 3.97 (dd, J=9.4, 4.5 Hz, 1H), 3.74 (s, 3H), 2.95 (ddd, J=16.1, 8.7, 7.2 Hz, 1H), 2.85 (ddd, J=16.3, 9.0, 4.8 Hz, 1H), 2.39 (dtd, J=13.1, 9.2, 7.2 Hz, 1H), 2.15 (tt, J=8.6, 4.5 Hz, 1H). MS (ESI+) m/z 271 (M+H⁺) —Br doublet.

Example I-19C 4-bromo-7-methoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-19B (154 mg, 0.568 mmol), naphthalene-1-sulfonamide (118 mg, 0.568 mmol), ((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (218 mg, 1.136 mmol) and N,N-dimethylpyridin-4-amine (76 mg, 0.625 mmol) were dissolved in dimethylacetamide (2.5 mL). The reaction was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL) and diluted with ethyl acetate (75 mL). The organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 9.65 (s, 1H), 8.47 (dt, J=7.4, 1.0 Hz, 1H), 8.43-8.35 (m, 1H), 8.12-8.05 (m, 1H), 7.97-7.88 (m, 1H), 7.62-7.51 (m, 3H), 7.32 (d, J=8.6 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 4.03 (dd, J=9.0, 1.8 Hz, 1H), 3.95 (s, 3H), 2.91-2.70 (m, 2H), 2.54 (ddt, J=12.8, 7.6, 2.3 Hz, 1H), 2.17-1.96 (m, 1H). MS (APCI+) m/z 462 (M+H⁺).

Example I-20 (6S)-6-methyl-N-(naphthalene-1-sulfonyl)-7,8-dihydro-2H,6H-indeno[4,5-d][1,3]dioxole-6-carboxamide

Into a 4 mL vial was weighed (6S)-6-methyl-7,8-dihydrocyclopenta[g][1,3]benzodioxole-6-carboxylic acid (9.03 mg, 0.036 mmol). A stock solution of N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (0.27 M in dichloromethane, 300 μL, 0.08 mmol, 2.0 equivalents), and N,N-dimethylpyridin-4-amine (0.15 M in dichloromethane, 300 μL, 0.05 mmol, 1.1 equivalents) was added. A slurry of naphthalene-1-sulfonamide (0.15 M in dichloromethane, 3000, 0.04 mmol, 1.0 equivalent) was added and the reaction stirred for 16 hours at room temperature. The solvent was removed under a stream of nitrogen. The residue was reconstituted in acetonitrile and was purified using preparative reverse phase HPLC/MS method TFA8 to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.59-8.51 (m, 1H), 8.27 (t, J=7.2 Hz, 2H), 8.14-8.07 (m, 1H), 7.75-7.65 (m, 3H), 6.63 (d, J=7.9 Hz, 1H), 6.50 (d, J=7.9 Hz, 1H), 5.96-5.90 (m, 2H), 2.76-2.63 (m, 1H), 2.63-2.55 (m, 1H), 2.46-2.34 (m, 1H), 1.88-1.76 (m, 1H), 1.28 (s, 3H). MS (APCI+) m/z 410.0 (M+H)⁺.

Example I-21 (6R)-6-methyl-N-(naphthalene-1-sulfonyl)-7,8-dihydro-2H,6H-indeno[4,5-d][1,3]dioxole-6-carboxamide

Into a 4 mL vial was weighed (6R)-6-methyl-7,8-dihydrocyclopenta[g][1,3]benzodioxole-6-carboxylic acid (9.03 mg, 0.036 mmol). A stock solution of N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (0.27 M in dichloromethane, 300 μL, 0.08 mmol, 2.0 equivalents), and N,N-dimethylpyridin-4-amine (0.15 M in dichloromethane, 300 μL, 0.05 mmol, 1.1 equivalents) was added. A slurry of naphthalene-1-sulfonamide (0.15 M in dichloromethane, 3000, 0.04 mmol, 1.0 equivalent) was added and the reaction stirred for 16 hours at room temperature. The solvent was removed under a stream of nitrogen. The residue was reconstituted in acetonitrile and purified using preparative reverse phase HPLC/MS method TFA8 to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.59-8.51 (m, 1H), 8.31-8.23 (m, 2H), 8.15-8.06 (m, 1H), 7.76-7.64 (m, 3H), 6.63 (d, J=7.9 Hz, 1H), 6.50 (d, J=7.9 Hz, 1H), 5.96-5.90 (m, 2H), 2.76-2.63 (m, 1H), 2.63-2.54 (m, 1H), 2.46-2.34 (m, 1H), 1.88-1.76 (m, 1H), 1.28 (s, 3H). MS (APCI+) m/z 410.0 (M+H)⁺.

Example I-22 (1S)-6-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was weighed (1S)-6-methoxy-1-methyl-indane-1-carboxylic acid (16.4 mg, 0.079 mmol). A stock solution of N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (0.39 M in dichloromethane, 400 μL, 0.16 mmol, 2.0 equivalents), and N,N-dimethylpyridin-4-amine (0.22 M in dichloromethane, 400 μL, 0.088 mmol, 1.1 equivalents) was added. A slurry of naphthalene-1-sulfonamide (0.20 M in dichloromethane, 400 μL, 0.08 mmol, 1.0 equivalent) was added and the reaction stirred for 16 hours at room temperature. The solvent was removed under a stream of nitrogen. The residue was reconstituted in acetonitrile and purified using preparative reverse phase HPLC/MS method TFA8 to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.61-8.53 (m, 1H), 8.31-8.23 (m, 2H), 8.14-8.05 (m, 1H), 7.73-7.63 (m, 3H), 7.03 (d, J=8.3 Hz, 1H), 6.71 (dd, J=8.2, 2.5 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 3.62 (s, 3H), 2.74-2.62 (m, 1H), 2.63-2.54 (m, 1H), 2.44-2.32 (m, 1H), 1.87-1.75 (m, 1H), 1.33 (s, 3H). MS (APCI+) m/z 396.1 (M+H)⁺.

Example I-23 (1R)-6-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was weighed (1R)-6-methoxy-1-methyl-indane-1-carboxylic acid (16.4 mg, 0.079 mmol). A stock solution of N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (0.39 M in dichloromethane, 400 μL, 0.16 mmol, 2.0 equivalents), and N,N-dimethylpyridin-4-amine (0.22 M in dichloromethane, 400 μL, 0.088 mmol, 1.1 equivalents) was added. A slurry of naphthalene-1-sulfonamide (0.20 M in dichloromethane, 400 μL, 0.08 mmol, 1.0 equivalent) was added and the reaction stirred for 16 hours at room temperature. The solvent was removed under a stream of nitrogen. The residue was reconstituted in acetonitrile and was purified using preparative reverse phase HPLC/MS method TFA8 to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.60-8.53 (m, 1H), 8.31-8.23 (m, 2H), 8.14-8.05 (m, 1H), 7.73-7.63 (m, 3H), 7.03 (d, J=8.2 Hz, 1H), 6.71 (dd, J=8.2, 2.5 Hz, 1H), 6.66 (d, J=2.5 Hz, 1H), 3.62 (s, 3H), 2.74-2.54 (m, 2H), 2.44-2.32 (m, 1H), 1.87-1.75 (m, 1H), 1.34 (s, 3H). MS (APCI+) m/z 396.1 (M+H)⁺.

Example I-24 N-(naphthalene-1-sulfonyl)-6,7,8,9-tetrahydro-2H-naphtho[1,2-d][1,3]dioxole-6-carboxamide

Into a 4 mL vial was weighed 6,7,8,9-tetrahydro-naphtho[1,2-d][1,3]dioxole-6-carboxylic acid (17.5 mg, 0.079 mmol). A stock solution of N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (0.39 M in dichloromethane, 400 μL, 0.16 mmol, 2.0 equivalents), and N,N-dimethylpyridin-4-amine (0.22 M in dichloromethane, 400 μL, 0.088 mmol, 1.1 equivalents) was added. A slurry of naphthalene-1-sulfonamide (0.20 M in dichloromethane, 400 μL, 0.08 mmol, 1.0 equivalent) was added and the reaction stirred for 16 hours at room temperature. The solvent was removed under a stream of nitrogen. The residue was reconstituted in acetonitrile and was purified using preparative reverse phase HPLC/MS method TFA8 to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.68-8.61 (m, 1H), 8.32-8.23 (m, 2H), 8.17-8.10 (m, 1H), 7.86-7.79 (m, 1H), 7.78-7.71 (m, 1H), 7.68 (t, J=7.8 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H), 6.12 (d, J=8.0 Hz, 1H), 5.88 (d, J=10.9 Hz, 2H), 3.65 (t, J=6.1 Hz, 1H), 2.48-2.35 (m, 2H), 1.79-1.60 (m, 2H), 1.52-1.30 (m, 2H). MS (APCI+) m/z 410.0 (M+H)⁺.

Example I-26 (1S)-7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was added 7-chloro-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (67.2 mg, 0.319 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (122 mg, 0.638 mmol), and N,N-dimethylpyridin-4-amine (42.9 mg, 0.351 mmol) in dichloromethane (0.5 mL). Naphthalene-1-sulfonamide (66.1 mg, 0.319 mmol) was added neat and the mixture was stirred at room temperature for 16 hours. The solvent was removed under a stream of nitrogen. The residue was reconstituted in acetonitrile and purified using preparative reverse phase HPLC/MS method TFA8 to provide the racemate of title compound. The material was separated by chiral preparative SFC chromatography using a CHIRALPAK OJ-H, column size 21×250 mm, 5 micron, serial Number: OJH0SAND002-011141, using a concentration of 15 mg/mL in methanol at a flow rate of 56 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.50-8.41 (m, 1H), 8.33-8.25 (m, 2H), 8.10 (dd, J=7.3, 1.9 Hz, 1H), 7.74-7.61 (m, 3H), 7.58-7.51 (m, 1H), 7.37-7.22 (m, 3H), 7.16 (td, J=7.8, 1.4 Hz, 1H), 6.97-6.91 (m, 2H), 6.89-6.81 (m, 1H), 6.76 (d, J=8.1 Hz, 1H), 4.99 (d, J=9.5 Hz, 1H), 4.36 (d, J=9.6 Hz, 1H). MS (APCI+) m/z 430.0 (M+H)⁺.

Example I-27 (1R)-7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-27 was isolated as the second enantiomer from the preparative SFC separation described in Example I-26. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.50-8.41 (m, 1H), 8.33-8.25 (m, 2H), 8.10 (dd, J=7.3, 1.9 Hz, 1H), 7.74-7.61 (m, 3H), 7.58-7.51 (m, 1H), 7.37-7.22 (m, 3H), 7.16 (td, J=7.8, 1.4 Hz, 1H), 6.97-6.91 (m, 2H), 6.89-6.81 (m, 1H), 6.76 (d, J=8.1 Hz, 1H), 4.99 (d, J=9.5 Hz, 1H), 4.36 (d, J=9.6 Hz, 1H). MS (APCI+) m/z 400 (M+H)⁺.

Example I-28 4-bromo-1-ethyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a cooled (ice bath) solution of Example I-19B (30 mg, 0.065 mmol) in tetrahydrofuran (0.5 mL), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.029 mL) and iodoethane (0.012 mL, 0.143 mmol) was added a solution of 1 M lithium bis(trimethylsilyl)amide (0.196 mL, 0.196 mmol) in tetrahydrofuran dropwise. The reaction mixture was stirred in the cold bath for five minutes before the bath was removed. Stirring was continued at room temperature. After 40 minutes, additional iodoethane (0.012 mL, 0.143 mmol) and 1 M lithium bis(trimethylsilyl)amide (0.196 mL, 0.196 mmol) in tetrahydrofuran were added. After the mixture had been stirred 5 hours total, the reaction was quenched with 1 M aqueous citric acid (300 μL). The organics were separated and the aqueous layer was extracted with 1 mL of ethyl acetate. The combined organics were dried in a vacuum oven and the crude material was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to give the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 9.71 (s, 1H), 8.50 (dd, J=7.4, 1.3 Hz, 1H), 8.41-8.32 (m, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.94 (dd, J=7.2, 2.1 Hz, 1H), 7.65-7.59 (m, 1H), 7.59-7.51 (m, 2H), 7.39 (d, J=8.7 Hz, 1H), 6.71 (d, J=8.7 Hz, 1H), 3.93 (s, 3H), 2.83-2.58 (m, 3H), 2.16 (dq, J=14.7, 7.4 Hz, 1H), 1.82-1.66 (m, 2H), 0.46 (t, J=7.5 Hz, 3H). MS (ESI+) m/z 488 (M+H)⁺.

Example I-29 4-chloro-1-(cyclopropylmethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of Example I-8B (15 mg, 0.04 mmol, 1.0 equivalent) in 30 μl of 1,3-dimethyl-2-imidazolidinone and 200 μl of tetrahydrofuran was added LiHMDS (lithium bis(trimethylsilyl)amide) (1 M in tetrahydrofuran, 120 μL, 0.12 mmol, 3.0 equivalents) at 0° C. over 5 minutes. After 10 minutes (bromomethyl)cyclopropane (12.1 mg, 0.09 mmol, 2.3 equivalents) was added in 200 μl of tetrahydrofuran. The reaction was degassed, flushed with N₂ and allowed to stir at 0° C. for another 10 minutes, and stirred at room temperature for 2 hours. The reaction was purified via preparative reverse phase HPLC/MS method TFA8 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.63-8.56 (m, 1H), 8.22-8.17 (m, 2H), 8.06-8.01 (m, 1H), 7.65-7.60 (m, 3H), 7.24-7.07 (m, 3H), 2.83-2.72 (m, 2H), 2.46-2.31 (m, 1H), 2.10 (s, 1H), 1.96-1.86 (m, 1H), 1.53-1.48 (m, 1H), 0.25-0.20 (m, 1H), 0.14-0.07 (m, 2H), −0.15-−0.20 (m, 2H). MS (APCI+) m/z 440.0 (M+H)⁺.

Example I-30 1-butyl-4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of Example I-8B (15 mg, 0.04 mmol, 1.0 equivalent) in 30 μl of DMI (1,3-dimethyl-2-imidazolidinone) and 200 μl of tetrahydrofuran was added LiHMDS (lithium bis(trimethylsilyl)amide) (1 M in tetrahydrofuran, 120 μL, 0.12 mmol, 3.0 equivalents) at 0° C. over 5 minutes. After 10 minutes bromobutane (12.3 mg, 0.09 mmol, 2.3 equivalents) was added in 200 μl of tetrahydrofuran. The reaction was degassed, flushed with N₂, was allowed to stir at 0° C. for another 10 minutes, and stirred at room temperature for 2 hours. The reaction mixture was purified via preparative reverse phase HPLC/MS method TFA8 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.62 (d, J=8.0 Hz, 1H), 8.25-8.20 (m, 2H), 8.09-8.04 (m, 1H), 7.68-7.63 (m, 3H), 7.33-7.26 (m, 1H), 7.19 (dt, J=15.3, 7.7 Hz, 2H), 2.76 (s, 2H), 2.48-2.29 (m, 1H), 2.06-1.95 (m, 1H), 1.89 (s, 1H), 1.54-1.49 (m, 1H), 1.07-0.95 (m, 2H), 0.73-0.68 (m, 2H), 0.57 (t, J=7.3 Hz, 3H). MS (APCI+) m/z 442.0 (M+H)⁺.

Example I-31 4-chloro-1-ethyl-N-(8-hydroxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-17A (17.3 mg, 0.08 mmol, 1.0 equivalent), EDC HCl (N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride) (29.6 mg, 0.15 mmol, 2.0 equivalents) and DMAP (4-dimethylaminopyridine) (10.4 mg, 0.08 mmol, 1.1 equivalents) were dissolved in dichloromethane (0.3 mL). The mixture was added to a solution of 8-hydroxynaphthalene-1-sulfonamide (20.0 mg, 0.09 mmol, 1.2 equivalents) in dichloromethane (0.3 mL). The reaction was stirred for 16 hours at room temperature. The solvent was removed under a stream of N₂. The residue was reconstituted in acetonitrile and was purified using preparative reverse phase HPLC/MS method TFA10 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.31 (dd, J=7.5, 1.3 Hz, 1H), 8.16 (dd, J=8.4, 1.3 Hz, 1H), 7.63-7.51 (m, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.33-7.18 (m, 3H), 7.14 (dd, J=7.5, 1.4 Hz, 1H), 2.91-2.71 (m, 2H), 2.49-2.37 (m, 1H), 2.11-1.97 (m, 2H), 1.82-1.68 (m, 1H), 0.61 (t, J=7.3 Hz, 3H). MS (APCI+) m/z 430.0 (M+H)⁺.

Example I-32 8-bromo-5-ethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Example I-32A 8-bromo-5-hydroxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

A solution of 8-bromo-5-methoxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (Example I-15, 500 mg, 1.054 mmol) in dichloromethane (15 mL) under N₂ at 0° C. was treated dropwise with 1 M BBr₃ in dichloromethane (3162 μl, 3.16 mmol), stirred at 0° C. for 1 hour, stirred at room temperature for 1 hour, cooled to 0° C., diluted with dichloromethane (80 mL), treated with 0.5 M aqueous HCl (100 mL), and transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (30 mL). The combined dichloromethane layers were treated with methanol (˜10 mL) to dissolve some precipitate that had formed. The homogenous solution was dried (MgSO₄), filtered, and concentrated. The residue was treated with dichloromethane (˜20 mL) and heated to dissolve part of the material on the sides of the flask and was allowed to stand at room temperature for 16 hours. The material was collected by filtration to provide the title compound. The filtrate was concentrated and the residue was taken up in dichloromethane (˜3 mL) and the resulting material was collected by filtration to provide additional title compound. The combined material was dried under vacuum with heating (50° C.) for ˜30 minutes to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.67 (s, 1H), 9.51 (bs, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.24 (dd, J=7.4, 1.2 Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.75 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.70-7.63 (m, 2H), 6.94 (d, J=8.6 Hz, 1H), 6.53 (d, J=8.6 Hz, 1H), 3.75 (dd, J=6.3, 2.4 Hz, 1H), 2.52-2.44 (m, 1H), 2.22 (ddd, J=17.5, 11.2, 6.1 Hz, 1H), 1.90 (d, J=12.7 Hz, 1H), 1.73 (dddd, J=13.5, 9.0, 6.5, 3.2 Hz, 1H), 1.49-1.40 (m, 1H), 1.10-0.97 (m, 1H). MS (ESI+) m/z 460,462 (M+H)⁺.

Example I-32B 8-bromo-5-ethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

A solution of Example I-32A (8-bromo-5-hydroxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide) (15 mg, 0.033 mmol) in N,N-dimethylformamide (0.3 mL) was treated with ethyl iodide (15.80 μl, 0.196 mmol), treated with cesium carbonate (53.1 mg, 0.163 mmol), stirred at room temperature for 30 minutes, and filtered. The filtrate was directly purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-40% (over 15 minutes) gradient of acetonitrile in 0.1% TFA] to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.71 (s, 1H), 8.69 (d, J=8.6 Hz, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.24 (dd, J=7.4, 1.1 Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.76 (ddd, J=8.5, 6.9, 1.3 Hz, 1H), 7.70-7.62 (m, 2H), 7.10 (d, J=8.7 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 3.99-3.86 (m, 2H), 3.78 (dd, J=6.2, 2.3 Hz, 1H), 2.56-2.49 (m, 1H), 2.25 (ddd, J=17.7, 11.3, 6.2 Hz, 1H), 1.91 (d, J=12.3 Hz, 1H), 1.74 (tdd, J=13.5, 6.5, 2.5 Hz, 1H), 1.50-1.42 (m, 1H), 1.26 (t, J=6.9 Hz, 3H), 1.09-0.96 (m, 1H). MS (APCI+) m/z 488,490 (M+H)⁺.

Example I-33 8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

In a 4 mL vial was added 8-bromo-5-methoxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (Example I-15, 35 mg, 0.074 mmol) and PEPPSI IPentCl ([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II)) (6.35 mg, 7.38 μmol) in tetrahydrofuran (0.5 mL). Cyclobutylzinc(II) bromide (0.738 mL, 0.369 mmol) was added. The reaction was stirred at room temperature for 3 hours, and heated at 60° C. for 16 hours. The sample was directly purified using preparative HPLC/MS TFA8 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.76 (d, J=8.7 Hz, 1H), 8.38-8.23 (m, 2H), 8.23-8.08 (m, 1H), 7.93-7.82 (m, 1H), 7.82-7.73 (m, 1H), 7.73-7.58 (m, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 3.73 (d, J=3.4 Hz, 1H), 3.70 (s, 3H), 2.68-2.57 (m, 2H), 2.37-2.22 (m, 1H), 2.21-2.11 (m, 1H), 2.03-1.90 (m, 1H), 1.84-1.49 (m, 4H), 1.41 (q, J=9.5, 9.0 Hz, 1H), 1.31-0.95 (m, 3H). MS (APCI+) m/z 450.0 (M+H)⁺.

Example I-34 8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Example I-34A 8-chloro-1-ethyl-1,2,3,4-tetrahydronaphthalene-1-carbonitrile

To a cooled (ice bath) solution of 8-chloro-1,2,3,4-tetrahydronaphthalene-1-carbonitrile (514 mg, 2.68 mmol, Example I-2A) and ethyl iodide (0.650 mL, 8.05 mmol) in tetrahydrofuran (2 mL) was added 1 M potassium tert-butoxide in tetrahydrofuran (2.68 mL, 2.68 mmol). The ice bath was removed. N,N-Dimethylformamide (1.5 mL) was added until everything dissolved. After 1 hour, additional 1 M potassium tert-butoxide in tetrahydrofuran (2.68 mL, 2.68 mmol) was added and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with water, diluted with methyl tert-butyl ether (90 mL), and acidified with 1 M aqueous HCl (˜2 mL). The methyl tert-butyl ether layer was separated, dried over sodium sulfate, filtered, concentrated and chromatographed using a 12 g silica gel cartridge eluting with 5-50% ethyl acetate in heptane over 20 minutes to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.28 (d, J=7.5 Hz, 1H), 7.15 (t, J=7.7 Hz, 1H), 7.06 (dq, J=7.6, 1.1 Hz, 1H), 2.92-2.77 (m, 2H), 2.44-2.32 (m, 1H), 2.32-2.18 (m, 2H), 1.95-1.73 (m, 3H), 1.11 (t, J=7.4 Hz, 3H).

Example I-34B 8-chloro-1-ethyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-34A (0.550 g, 2.503 mmol) was dissolved in ethanol (5 mL). A solution of sodium hydroxide (0.778 g, 19.45 mmol) in water (5.00 mL) was added, and the resulting mixture was heated at 80° C. for 72 hours. The solvent was reduced in volume and the resulting aqueous layer was diluted with water (10 mL) and extracted with 100 mL of methyl tert-butyl ether. The extracts were dried over sodium sulfate, and filtered. The solvent was removed in vacuo to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.30-7.22 (m, 1H), 7.18-7.12 (m, 1H), 7.07 (td, J=7.5, 1.3 Hz, 1H), 5.26 (s, 2H), 2.90-2.80 (m, 2H), 2.45-2.33 (m, 1H), 2.32-2.21 (m, 2H), 1.97-1.73 (m, 3H), 1.12 (t, J=7.4 Hz, 3H). MS (ESI+) 238 m/z (M+H⁺).

Example I-34C 8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-34B (0.541 g, 2.276 mmol) was dissolved in tetrahydrofuran (2.5 mL) and sodium hydride (0.182 g, 4.55 mmol) as a 60% dispersion in mineral oil was added in portions. After stirring at room temperature for 60 minutes, naphthalene-1-sulfonyl chloride (0.516 g, 2.276 mmol) was added in portions. The reaction was warmed at 30° C. for 2 hours. The solvent was reduced under a stream of nitrogen. The reaction was diluted with methyl tert-butyl ether and quenched with 1 mL of 1 N aqueous HCl and water (1 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was triturated with 50% methyl tert-butyl ether/heptanes and the resulting precipitate was washed with heptanes to give the title compound. ¹H NMR (500 MHz, Chloroform-d) δ ppm 8.57 (dt, J=7.4, 1.0 Hz, 1H), 8.43-8.33 (m, 1H), 8.19-8.13 (m, 1H), 8.04-7.94 (m, 1H), 7.88 (s, 1H), 7.71-7.57 (m, 3H), 7.20-7.06 (m, 2H), 7.00 (dd, J=7.6, 1.6 Hz, 1H), 2.86 (dt, J=16.4, 5.3 Hz, 1H), 2.79-2.70 (m, 1H), 2.37-2.26 (m, 1H), 1.96 (ddd, J=13.9, 10.3, 3.6 Hz, 1H), 1.91-1.68 (m, 4H), 0.62-0.49 (m, 3H). MS (APCI+) m/z 428 (M+H⁺).

Example I-35 4-chloro-N-(naphthalene-1-sulfonyl)-1-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydro-1H-indene-1-carboxamide

To a solution of Example I-8B (20 mg, 0.05 mmol, 1.0 equivalent) in 30 μl of DMI (1,3-dimethyl-2-imidazolidinone) and 200 μl of tetrahydrofuran was added LiHMDS (lithium bis(trimethylsilyl)amide) (1 M in tetrahydrofuran, 155 μL, 0.15 mmol, 3.0 equivalents) at 0° C. over 5 minutes. After 10 minutes, 2-(chloromethyl)-6-(trifluoromethyl)pyridine (23.3 mg, 0.12 mmol, 2.3 equivalents) was added in 200 μl of tetrahydrofuran. The reaction was degassed, flushed with N₂ and allowed to stir at 0° C. for another 10 minutes, and stirred at room temperature for 2 hours. The reaction was purified via preparative reverse phase HPLC/MS method TFA6. Impurities were present after TFA purification and the sample was purified via preparative reverse phase HPLC/MS method AA6 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.61 (d, J=8.5 Hz, 1H), 8.15 (d, J=7.3 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.60-7.51 (m, 3H), 7.50-7.42 (m, 2H), 7.14-7.05 (m, 3H), 7.04-6.96 (m, 1H), 3.56 (d, J=13.9 Hz, 1H), 3.15 (d, J=14.1 Hz, 1H), 2.82-2.70 (m, 1H), 2.51-2.36 (m, 2H), 2.19-2.08 (m, 1H). MS (APCI+) m/z 544.9 (M+H)⁺.

Example I-36 4-chloro-1-[(6-chloropyridin-3-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of Example I-8B (20 mg, 0.05 mmol, 1.0 equivalent) in 30 μl of DMI (1,3-dimethyl-2-imidazolidinone) and 200 μl of tetrahydrofuran was added LiHMDS (1 M in tetrahydrofuran, 155 μL, 0.15 mmol, 3.0 equivalents) at 0° C. over 5 minutes. After 10 minutes, 2-chloro-5-(chloromethyl)pyridine (18.8 mg, 0.12 mmol, 2.3 equivalents) was added in 200 μl of tetrahydrofuran. The reaction was degassed, flushed with N₂, allowed to stir at 0° C. for another 10 minutes, and stirred at room temperature for 2 hours. The reaction was purified via preparative reverse phase HPLC/MS method TFA6. Impurities were present after TFA purification and the sample was purified via preparative reverse phase HPLC/MS method AA6 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.66 (d, J=8.5 Hz, 1H), 8.12-8.05 (m, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.95-7.85 (m, 2H), 7.55-7.45 (m, 2H), 7.45-7.36 (m, 1H), 7.23 (dd, J=8.3, 2.5 Hz, 1H), 7.12 (d, J=7.5 Hz, 2H), 7.09-7.00 (m, 1H), 6.92 (d, J=8.2 Hz, 1H), 3.30 (d, J=13.6 Hz, 1H), 2.84 (d, J=13.6 Hz, 1H), 2.81-2.71 (m, 1H), 2.52-2.40 (m, 2H), 1.90-1.78 (m, 1H). MS (APCI+) m/z 510.9 (M+H)⁺.

Example I-37 4-chloro-1-[(6-methoxypyridin-2-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of Example I-8B (20 mg, 0.05 mmol, 1.0 equivalent) in 30 μl of DMI (1,3-dimethyl-2-imidazolidinone) and 200 μl of tetrahydrofuran was added LiHMDS (1 M in tetrahydrofuran, 155 μL, 0.15 mmol, 3.0 equivalents) at 0° C. over 5 minutes. After 10 minutes, 2-(chloromethyl)-6-methoxypyridine (18.8 mg, 0.12 mmol, 2.3 equivalents) was added in 200 μl of tetrahydrofuran. The reaction was degassed, flushed with N₂, allowed to stir at 0° C. for another 10 minutes, and stirred at room temperature for 2 hours. The reaction was purified via preparative reverse phase HPLC/MS method TFA6. Impurities were present after TFA purification and the sample was purified via preparative reverse phase HPLC/MS method AA6 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.73 (d, J=8.7 Hz, 1H), 8.05-7.98 (m, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.88-7.82 (m, 1H), 7.49-7.41 (m, 2H), 7.40-7.31 (m, 1H), 7.26 (dd, J=7.3, 1.4 Hz, 1H), 7.23-7.15 (m, 1H), 7.08-6.95 (m, 2H), 6.46 (d, J=7.3 Hz, 1H), 6.41 (d, J=8.0 Hz, 1H), 3.63 (s, 3H), 3.38 (d, J=13.6 Hz, 1H), 2.98 (d, J=13.6 Hz, 1H), 2.82-2.69 (m, 1H), 2.65-2.53 (m, 1H), 2.44-2.33 (m, 1H), 2.08-1.96 (m, 1H). MS (APCI+) m/z 506.9 (M+H)⁺.

Example I-38 4-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of Example I-8B (20 mg, 0.05 mmol, 1.0 equivalent) in 30 μl of DMI (1,3-dimethyl-2-imidazolidinone) and 200 μl of tetrahydrofuran was added LiHMDS (1 M in tetrahydrofuran, 155 μL, 0.15 mmol, 3.0 equivalents) at 0° C. over 5 minutes. After 10 minutes, methyliodide (16.9 mg, 0.12 mmol, 2.3 equivalents) was added in 200 μl of tetrahydrofuran. The reaction was degassed, flushed with N₂, allowed to stir at 0° C. for another 10 minutes, and stirred at room temperature for 2 hours. The reaction was purified via preparative reverse phase HPLC/MS method TFA8. Impurities were present after TFA purification and the sample was purified via preparative reverse phase HPLC/MS method AA6 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.65 (d, J=7.2 Hz, 1H), 8.11 (dd, J=25.8, 7.7 Hz, 2H), 7.97 (d, J=8.0 Hz, 1H), 7.60-7.51 (m, 3H), 7.16-7.09 (m, 1H), 7.08-6.95 (m, 2H), 2.78 (t, J=7.3 Hz, 2H), 2.52-2.45 (m, 1H), 1.85-1.73 (m, 1H), 1.30 (s, 3H). MS (APCI+) m/z 400.0 (M+H)⁺.

Example I-39 4-chloro-N-(5-chloronaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was weighed Example I-17A (30.0 mg, 0.13 mmol). A stock solution of N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (0.26 M in dichloromethane, 1.0 mL, 0.26 mmol, 2.0 equivalents), and N,N-dimethylpyridin-4-amine (0.15 M in dichloromethane, 1.0 mL, 0.15 mmol, 1.1 equivalents) was added. 5-Chloronaphthalene-1-sulfonamide (32.3 mg, 0.13 mmol, 1.0 equivalent) was added and the reaction was stirred for 16 hours at room temperature. The solvent was removed under a stream of nitrogen. The residue was reconstituted in acetonitrile and was purified using preparative reverse phase HPLC/MS method TFA8 to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.63-8.53 (m, 2H), 8.41-8.34 (m, 1H), 7.91-7.82 (m, 2H), 7.73-7.64 (m, 1H), 7.27-7.10 (m, 3H), 2.86-2.71 (m, 2H), 2.37-2.27 (m, 1H), 2.07-1.88 (m, 2H), 1.70-1.56 (m, 1H), 0.48 (t, J=7.3 Hz, 3H). MS (APCI+) m/z 447.9 (M+H)⁺.

Example I-40 8-bromo-N-(naphthalene-1-sulfonyl)-5-[(propan-2-yl)oxy]-1,2,3,4-tetrahydronaphthalene-1-carboxamide

A solution of Example I-32A (8-bromo-5-hydroxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide) (14.7 mg, 0.032 mmol) in N,N-dimethylformamide (0.2 mL) was treated with 2-bromopropane (18 mg, 0.146 mmol), treated with cesium carbonate (60 mg, 0.184 mmol), stirred at room temperature for 30 minutes, heated to 50° C. for 30 minutes, cooled, diluted with N,N-dimethylformamide, filtered, and directly purified the filtrate by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-40% (over 15 minutes) gradient of acetonitrile in 0.1% TFA] to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.71 (s, 1H), 8.68 (d, J=8.3 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.23 (dd, J=7.4, 1.1 Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.75 (ddd, J=8.5, 7.0, 1.3 Hz, 1H), 7.70-7.62 (m, 2H), 7.08 (d, J=8.8 Hz, 1H), 6.70 (d, J=8.9 Hz, 1H), 4.48 (p, J=6.0 Hz, 1H), 3.77 (dd, J=6.1, 2.2 Hz, 1H), 2.54-2.46 (m, 1H), 2.22 (ddd, J=17.7, 11.3, 6.1 Hz, 1H), 1.94-1.87 (m, 1H), 1.79-1.69 (m, 1H), 1.50-1.42 (m, 1H), 1.21-1.17 (m, 6H), 1.09-0.96 (m, 1H). MS (APCI+) m/z 502, 504 (M+H)⁺.

Example I-41 5-bromo-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Example I-41A 5-bromo-8-methoxy-3,4-dihydronaphthalene-1-carbonitrile

A flask containing 1.6 M n-butyllithium in hexanes (4.66 mL, 7.46 mmol) was cooled to −78° C. under N₂ and treated dropwise with a solution of trimethylsilyl cyanide (1 mL, 7.46 mmol) in tetrahydrofuran (5 mL). The mixture was allowed to warm to room temperature and was stirred for 1 hour. The mixture was diluted with heptanes and the material was collected by filtration to provide a material which contained LiCN. A solution of 5-bromo-8-methoxy-3,4-dihydronaphthalen-1(2H)-one (CAS#77259-96-2) (0.4 g, 1.568 mmol) in N,N-dimethylformamide (1.5 mL) was cooled to 0° C., treated with diethyl cyanophosphonate (0.476 mL, 3.14 mmol), and treated with 20 mg of the LiCN containing material from above. The mixture was stirred at room temperature for 90 minutes. The mixture was diluted with methyl tert-butyl ether (60 mL), washed with water (once with 30 mL, and once with 15 mL), washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was dissolved in toluene (10 mL), treated with para-toluenesulfonic acid monohydrate (0.030 g, 0.157 mmol), heated to 120° C. for 3 hours, cooled, and partitioned between methyl tert-butyl ether (50 mL) and saturated aqueous NaHCO₃ solution (˜15 mL). The methyl tert-butyl ether layer was washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was chromatographed on silica gel, eluting with 15% ethyl acetate in heptanes to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.45 (d, J=8.9 Hz, 1H), 6.97 (t, J=5.1 Hz, 1H), 6.72 (d, J=8.9 Hz, 1H), 3.89 (s, 3H), 2.92-2.82 (m, 2H), 2.41 (td, J=8.1, 5.2 Hz, 2H).

Example I-41B 5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile

A mixture of Example I-41A (5-bromo-8-methoxy-3,4-dihydronaphthalene-1-carbonitrile) (0.33 g, 1.249 mmol) in ethanol (10 mL) was treated with NaBH₄ (0.284 g, 7.50 mmol) and the mixture was heated to reflux for 20 minutes. The mixture was cooled and concentrated. The residue was partitioned between methyl tert-butyl ether (50 mL) and 1 M aqueous HCl (25 mL). The methyl tert-butyl ether layer was washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was chromatographed on silica gel, eluting with 15% ethyl acetate in heptane to provide the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 7.48 (d, J=8.8 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 4.10 (dd, J=5.4, 2.5 Hz, 1H), 3.89 (s, 3H), 2.94 (ddd, J=17.9, 5.3, 1.9 Hz, 1H), 2.57 (ddd, J=17.9, 11.4, 6.4 Hz, 1H), 2.31-2.24 (m, 1H), 2.09-1.92 (m, 2H), 1.79 (tdd, J=13.2, 5.5, 3.1 Hz, 1H).

Example I-41C 5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide

A suspension of Example I-41B (5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile) (101 mg, 0.380 mmol) in ethanol (1.2 mL) was treated with 3 M aqueous NaOH (1265 μl, 3.80 mmol) and heated to 80° C. for 16 hours. The mixture was cooled to room temperature and treated with a stream of N₂ to remove the ethanol. The residue was diluted with water (˜3 mL). The material was collected by filtration, washed with water and dried under vacuum with heating (50° C.) for 30 minutes to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 7.42 (d, J=8.7 Hz, 1H), 7.16 (bs, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.70 (bs, 1H), 3.71 (s, 3H), 3.68-3.65 (m, 1H), 2.73-2.63 (m, 1H), 2.56-2.45 (m, 1H), 1.99-1.90 (m, 1H), 1.81-1.65 (m, 3H). MS (APCI+) m/z 284,286 (M+H)⁺.

Example I-41D 5-bromo-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

A solution of Example I-41C (5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide) (19 mg, 0.067 mmol) in tetrahydrofuran (0.5 mL) was treated with a 60% dispersion of sodium hydride in mineral oil (5.88 mg, 0.147 mmol), stirred at room temperature for 45 minutes, cooled to 0° C., treated with a solution of 1-naphthalenesulfonyl chloride (16.67 mg, 0.074 mmol) in tetrahydrofuran (0.2 mL), stirred at room temperature for 10 minutes, heated to 68° C. for 75 minutes, cooled to 0° C., treated with acetic acid (5 drops), and concentrated with a stream of N₂. The residue was diluted with N,N-dimethylformamide to ˜1 mL volume, and was directly purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-40% (over 15 minutes) gradient of acetonitrile in 0.1% TFA] to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.52 (s, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.24 (dd, J=7.4, 1.1 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.84-7.79 (m, 1H), 7.71 (t, J=7.5 Hz, 1H), 7.69-7.64 (m, 1H), 7.34 (d, J=8.8 Hz, 1H), 6.55 (d, J=8.8 Hz, 1H), 3.72-3.68 (m, 1H), 2.95 (s, 3H), 2.55-2.37 (m, 2H), 1.82-1.65 (m, 2H), 1.47 (s, 1H), 1.32 (d, J=3.4 Hz, 1H). MS (APCI+) m/z 474,476 (M+H)⁺.

Example I-42 4-chloro-1-ethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-17A (50 mg, 0.223 mmol) was combined with a mixture of N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (85 mg, 0.445 mmol) and N,N-dimethylpyridin-4-amine (29.9 mg, 0.245 mmol) in dichloromethane (2.5 mL). After 30 minutes, quinoline-5-sulfonamide (46.3 mg, 0.223 mmol) (CAS#415913-05-2, Enamine) was added. The reaction was stirred at room temperature for 16 hours. The reaction was quenched with 1.0 mL of 2 N aqueous HCl and the mixture was put through an aqueous/organic separator tube. The crude organic material was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to give slightly impure product, which was subsequently washed with methanol to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.15 (s, 1H), 9.00 (dd, J=4.2, 1.6 Hz, 1H), 8.93 (dd, J=8.8, 1.5 Hz, 1H), 8.31 (d, J=7.8 Hz, 2H), 7.91 (t, J=8.0 Hz, 1H), 7.68 (dd, J=8.8, 4.2 Hz, 1H), 7.20-7.17 (m, 1H), 7.14-7.07 (m, 2H), 2.83-2.64 (m, 2H), 2.28 (ddd, J=13.1, 8.3, 6.4 Hz, 1H), 2.02-1.85 (m, 2H), 1.60 (dq, J=14.5, 7.3 Hz, 1H), 0.43 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 415 (M+H⁺).

Example I-43 N-(1-benzothiophene-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide Example I-43A benzo[b]thiophene-4-sulfonamide

A 1 M solution of di-n-butylmagnesium (4.69 mL, 4.69 mmol) in tetrahydrofuran and 1.6 M butyllithium (2.93 mL, 4.69 mmol) in heptanes were combined to give a thick suspension. The suspension was cooled (dry ice/acetone, about −20° C.), and a solution of 4-bromobenzo[b]thiophene (1.00 g, 4.69 mmol) (CAS#5118-13-8, Arkpharm) in tetrahydrofuran (5 mL) was added, keeping the internal temperature below −10° C. The reaction mixture was stirred at −10° C. for 1 hour. The cold biphasic mixture was added to a cooled solution of sulfuryl chloride (0.875 mL, 10.79 mmol) in toluene (12 mL) while stirring in a dry ice/acetone bath keeping the internal temperature under 10° C. The reaction was quenched with 30 mL of ammonium hydroxide and a precipitate formed. The solvent was reduced in vacuo and the aqueous suspension was filtered and washed with water and ether to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.25 (dt, J=8.2, 1.0 Hz, 1H), 7.99 (t, J=5.2 Hz, 1H), 7.93-7.88 (m, 1H), 7.85 (dd, J=7.5, 1.0 Hz, 1H), 7.52 (s, 2H), 7.48 (t, J=7.8 Hz, 1H). MS (ESI−) m/z 212 (M−H⁻).

Example I-43B N-(1-benzothiophene-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide

Example I-17A (60 mg, 0.267 mmol) was combined with a mixture of N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (102 mg, 0.534 mmol) and N,N-dimethylpyridin-4-amine (35.9 mg, 0.294 mmol) in dichloromethane (2.0 mL). After 30 minutes, Example I-43A (85 mg, 0.401 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction was quenched with 1.0 mL of 1 N aqueous HCl and the organic portions were purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.20 (dd, J=7.6, 1.0 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J=5.6 Hz, 1H), 7.62 (dd, J=5.6, 0.8 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.31-7.28 (m, 1H), 7.18 (t, J=7.7 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H), 2.94-2.84 (m, 1H), 2.83-2.73 (m, 1H), 2.33 (ddd, J=13.9, 8.7, 5.5 Hz, 1H), 2.01 (ddd, J=13.4, 8.9, 6.5 Hz, 1H), 1.86 (dt, J=14.8, 7.3 Hz, 1H), 1.77 (dq, J=14.5, 7.4 Hz, 1H), 0.67 (t, J=7.4 Hz, 3H). MS (APCI+) m/z 420 (M+H⁺).

Example I-44 4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (59.5 mg, 0.487 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (170 mg, 0.885 mmol) were combined in N,N-dimethylacetamide (2.0 mL). To the suspension was added Example I-19B (120 mg, 0.443 mmol). After 30 minutes, quinoline-5-sulfonamide (92 mg, 0.443 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction was quenched with 1 N aqueous HCl (1 mL), put through an aqueous/organic separator tube with dichloromethane and the organics were purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR (500 MHz, Chloroform-d) δ ppm 9.69 (s, 1H), 9.02 (d, J=4.1 Hz, 1H), 8.89 (ddd, J=8.8, 1.6, 0.9 Hz, 1H), 8.52 (dd, J=7.5, 1.2 Hz, 1H), 8.41 (dt, J=8.5, 1.1 Hz, 1H), 7.86 (dd, J=8.4, 7.5 Hz, 1H), 7.51 (dd, J=8.8, 4.2 Hz, 1H), 7.37 (dd, J=8.7, 0.6 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 4.07 (dd, J=8.9, 1.7 Hz, 1H), 4.02 (s, 3H), 2.91-2.76 (m, 2H), 2.64-2.55 (m, 1H), 2.14-2.04 (m, 1H). MS (ESI+) m/z 462 (M+H⁺).

Example I-45 8-bromo-5-(2-methoxyethoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-32A (20.0 mg, 0.05 mmol, 1.0 equivalent) was dissolved in N,N-dimethylformamide (0.4 mL). Cs₂CO₃ (82.2 mg, 0.25 mmol, 5.0 equivalents) was added, followed by 1-bromo-2-methoxyethane (0.4 M in N,N-dimethylformamide, 504 μL, 0.20 mmol, 4.0 equivalents). The reaction was stirred for 16 hours at 50° C. The reaction was filtered and was purified using preparative reverse phase HPLC/MS method TFA8 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.71-8.64 (m, 1H), 8.32-8.21 (m, 2H), 8.15-8.08 (m, 1H), 7.81-7.74 (m, 1H), 7.73-7.61 (m, 2H), 7.11 (d, J=8.8 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 4.07-3.92 (m, 2H), 3.80-3.75 (m, 1H), 3.61 (t, J=4.5 Hz, 2H), 3.27 (s, 3H), 2.59-2.55 (m, 1H), 2.34-2.20 (m, 1H), 1.97-1.89 (m, 1H), 1.83-1.69 (m, 1H), 1.53-1.45 (m, 1H), 1.08-1.00 (m, 1H). MS (APCI+) m/z 519.9 (M+H)⁺.

Example I-46 (1S)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-44 (43 mg) was separated by chiral preparative SFC chromatography using a CHIRALPAK IA, column size 21×250 mm, 5 micron, serial Number: IA00SALC001-812121, using a concentration of 4.1 mg/mL in methanol at a flow rate of 52 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.98 (dd, J=4.1, 1.6 Hz, 1H), 8.95 (d, J=8.9 Hz, 1H), 8.46-8.38 (m, 1H), 8.33 (d, J=8.4 Hz, 1H), 7.84-7.73 (m, 1H), 7.46 (dd, J=8.7, 4.2 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 6.59 (d, J=8.6 Hz, 1H), 4.05 (dd, J=9.0, 2.7 Hz, 1H), 3.79 (s, 3H), 2.98-2.74 (m, 2H), 2.53-2.41 (m, 1H), 2.16 (dq, J=13.3, 9.0 Hz, 1H). MS (APCI+) m/z 463 (M+H⁺), Br doublet. R_(T) (chiral SFC)=9.5 minutes. The absolute structure of the title compound was determined by X-ray crystallography.

Example I-47 (1R)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-44 (43 mg) was separated by chiral preparative SFC chromatography using a CHIRALPAK IA, column size 21×250 mm, 5 micron, serial Number: IA00SALC001-812121, using a concentration of 4.1 mg/mL in methanol at a flow rate of 52 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.98 (dd, J=4.2, 1.6 Hz, 1H), 8.92 (dt, J=8.8, 1.2 Hz, 1H), 8.45 (dd, J=7.5, 1.2 Hz, 1H), 8.34 (dt, J=8.3, 1.1 Hz, 1H), 7.80 (dd, J=8.5, 7.4 Hz, 1H), 7.46 (dd, J=8.7, 4.2 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.61 (d, J=8.6 Hz, 1H), 4.05 (dd, J=9.0, 2.5 Hz, 1H), 3.84 (s, 3H), 2.92-2.73 (m, 2H), 2.49 (ddt, J=13.6, 8.2, 2.9 Hz, 1H), 2.13 (dq, J=13.3, 9.2 Hz, 1H). MS (APCI+) m/z 461 (M+H)⁺, Br doublet. R_(T) (chiral SFC)=10.5 minutes.

Example I-48 (1S)-8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

A solution of 8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (Example I-15C, 1.51 g, 5.31 mmol) in tetrahydrofuran (50 mL) under N₂ was treated with 60% dispersion of sodium hydride in mineral oil (0.468 g, 11.69 mmol), stirred at room temperature for 1 hour, cooled to 0° C., treated dropwise with a solution of 1-naphthylene sulfonyl chloride (1.325 g, 5.85 mmol) in tetrahydrofuran (20 mL), stirred at room temperature for 1 hour, and heated to reflux for 16 hours. The mixture was cooled and concentrated to remove the majority of tetrahydrofuran. The mixture was treated with methyl tert-butyl ether (˜20 mL) and treated with 1 M aqueous HCl (15 mL). The mixture was extracted with more methyl tert-butyl ether (˜100 mL). The organic layer was washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was treated with methyl tert-butyl ether (˜15 mL) and swirled. Material started to precipitate. Heptanes (30-50 mL) were slowly added. The material was collected by filtration, washed with cold 5:1 heptanes:methyl tert-butyl ether and dried under vacuum with heating to 50° C. for 30 minutes to provide racemic 8-bromo-5-methoxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 12.71 (s, 1H), 8.69 (d, J=8.6 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.24 (dd, J=7.4, 0.9 Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.76 (ddd, J=8.4, 6.9, 1.2 Hz, 1H), 7.70-7.63 (m, 2H), 7.13 (d, J=8.7 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 3.78 (dd, J=6.9, 2.8 Hz, 1H), 3.69 (s, 3H), 2.55-2.47 (m, 1H), 2.25 (ddd, J=17.7, 11.3, 6.2 Hz, 1H), 1.95-1.88 (m, 1H), 1.74 (dddd, J=13.4, 8.8, 6.4, 3.2 Hz, 1H), 1.50-1.42 (m, 1H), 1.09-0.97 (m, 1H). LC/MS (APCI+) m/z 474.1 (M+H)⁺. The racemic material was separated by chiral preparative SFC chromatography using a CHIRALPAK AD-H, column size 21×250 mm, 5 micron, serial Number: ADHSAMA003-810291, using a concentration of 15 mg/mL in methanol at a flow rate of 45 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.70-8.62 (m, 1H), 8.30-8.19 (m, 2H), 8.13-8.06 (m, 1H), 7.79-7.72 (m, 1H), 7.70-7.60 (m, 2H), 7.12 (d, J=8.7 Hz, 1H), 6.69 (d, J=8.9 Hz, 1H), 3.67 (s, 3H), 2.50-2.44 (m, 2H), 2.31-2.17 (m, 1H), 1.95-1.87 (m, 1H), 1.76-1.71 (m, 1H), 1.49-1.44 (m, 1H), 1.06-0.98 (m, 1H). MS (APCI+) m/z 474.1 (M+H)⁺.

Example I-49 (1R)-8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-49 was isolated as the second enantiomer during the preparative SFC separation described in Example I-48. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.68 (d, J=8.4 Hz, 1H), 8.23-8.16 (m, 2H), 8.07 (d, J=8.2 Hz, 1H), 7.79-7.57 (m, 3H), 7.13 (d, J=8.7 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 3.68 (s, 3H), 2.50-2.45 (m, 2H), 2.31-2.17 (m, 1H), 1.95-1.90 (m, 1H), 1.73-1.68 (m, 1H), 1.47-1.42 (m, 1H), 1.08-1.03 (m, 1H). MS (APCI+) m/z 474.1 (M+H)⁺.

Example I-50 5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Example I-50A 5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

A solution of Example I-41B (5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile) (20 mg, 0.075 mmol) in ethylene glycol (0.3 mL) was treated with 50% aqueous KOH solution (230 mg, 2.050 mmol), heated to 150° C. for 2 hours, heated to 170° C. for 3 hours, cooled to room temperature and partitioned between methyl tert-butyl ether (˜30 mL) and 1 M aqueous HCl (˜10 mL). The methyl tert-butyl ether layer was washed with 0.1 M aqueous HCl (˜10 mL), washed with brine, dried (MgSO₄), filtered, and concentrated to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.43 (d, J=8.7 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 3.91-3.88 (m, 1H), 3.79 (s, 3H), 2.84 (dt, J=17.5, 5.2 Hz, 1H), 2.64 (dt, J=17.6, 7.4 Hz, 1H), 2.20-2.11 (m, 1H), 2.02-1.91 (m, 1H), 1.88-1.80 (m, 2H).

Example I-50B 5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

To a solution of Example I-50A (5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid) (20.5 mg, 0.072 mmol), EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (27.6 mg, 0.144 mmol) and 4-dimethylaminopyridine (9.66 mg, 0.079 mmol) in dichloromethane (0.3 mL) was added quinoline-5-sulfonamide (16.47 mg, 0.079 mmol). The mixture was stirred at room temperature for 16 hours, and concentrated with a stream of N₂. The residue was diluted with N,N-dimethylformamide and was directly purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1% TFA] to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.63 (s, 1H), 9.11-9.05 (m, 2H), 8.36 (d, J=8.4 Hz, 1H), 8.32 (dd, J=7.4, 1.0 Hz, 1H), 7.93 (dd, J=8.3, 7.7 Hz, 1H), 7.85 (dd, J=8.7, 4.2 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 6.56 (d, J=8.8 Hz, 1H), 3.70-3.67 (m, 1H), 2.98 (s, 3H), 2.58-2.38 (m, 2H), 1.84-1.74 (m, 1H), 1.72-1.64 (m, 1H), 1.56-1.46 (m, 1H), 1.40-1.28 (m, 1H). MS (APCI+) m/z 475,477 (M+H)⁺.

Example I-51 (1S)-4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-19C (70 mg) was separated by chiral preparative SFC chromatography using a Whelk-O (S,S), column size 21×250 mm, 5 micron, serial Number: 43170, using a concentration of 6.9 mg/mL in methanol at a flow rate of 25 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.58 (s, 1H), 8.65 (dd, J=8.6, 1.0 Hz, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.25 (d, J=7.5 Hz, 1H), 8.15-8.04 (m, 1H), 7.78 (t, J=7.7 Hz, 1H), 7.73-7.65 (m, 2H), 7.28 (dd, J=8.6, 0.7 Hz, 1H), 6.58 (d, J=8.7 Hz, 1H), 4.03 (dd, J=9.2, 5.6 Hz, 1H), 3.11 (s, 3H), 2.74 (t, J=7.5 Hz, 2H), 2.32-2.19 (m, 1H), 1.82 (dq, J=13.3, 7.0 Hz, 1H). MS (APCI+) m/z 460 (M+H⁺), Br doublet; R_(T) (chiral SFC)=4.4 minutes.

Example I-52 (1R)-4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-19C was separated by chiral preparative SFC chromatography using a Whelk-O (S,S), column size 21×250 mm, 5 micron, serial Number: 43170, using a concentration of 6.9 mg/mL in methanol at a flow rate of 25 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.57 (s, 1H), 8.65 (d, J=8.5 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H), 8.25 (d, J=7.4 Hz, 1H), 8.13 (d, J=8.1 Hz, 1H), 7.78 (t, J=7.4 Hz, 1H), 7.69 (dt, J=12.3, 7.9 Hz, 2H), 7.28 (d, J=8.6 Hz, 1H), 6.58 (d, J=8.7 Hz, 1H), 4.03 (dd, J=9.1, 5.6 Hz, 1H), 3.11 (s, 3H), 2.74 (t, J=7.5 Hz, 2H), 2.30-2.20 (m, 1H), 1.82 (dq, J=13.1, 7.1 Hz, 1H). MS (APCI+) m/z 460 (M+H)⁺, Br doublet; R_(T) (chiral SFC)=5.2 minutes.

Example I-53 4-bromo-7-ethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-53A 4-bromo-7-hydroxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A solution of Example I-19C (350 mg, 0.760 mmol) in dichloromethane (7 mL) under nitrogen at 0° C. was treated dropwise with 1 M boron tribromide in dichloromethane (2.243 mL, 2.243 mmol). The reaction was stirred at 0° C. for 30 minutes, allowed to stir at room temperature for 3 hours, cooled to 0° C., diluted with dichloromethane (10 mL), and treated with 1 M aqueous HCl (4 mL). The organics were separated. The aqueous layer was extracted with dichloromethane (30 mL). The combined dichloromethane layers were treated with methanol (˜1.5 mL) to dissolve some precipitate that had formed. The solution was dried (MgSO₄), filtered, and concentrated. The residual material was chromatographed using a 12 g silica gel cartridge with 100% ethyl acetate to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.48 (s, 1H), 9.74 (s, 1H), 8.67-8.58 (m, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.25 (dd, J=7.3, 1.2 Hz, 1H), 8.12 (dd, J=7.7, 1.4 Hz, 1H), 7.82-7.72 (m, 1H), 7.72-7.59 (m, 2H), 7.14 (d, J=8.5 Hz, 1H), 6.50 (d, J=8.5 Hz, 1H), 4.07 (dd, J=9.3, 4.6 Hz, 1H), 2.74-2.55 (m, 2H), 2.24-2.10 (m, 1H), 1.70 (d, J=5.0 Hz, 1H). MS (APCI+) m/z 446.0 (M+H)⁺.

Example I-53B 4-bromo-7-ethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A solution of Example I-53A (40 mg, 0.090 mmol) in N,N-dimethylformamide (0.5 mL) was treated with ethyl iodide (43.5 μl, 0.538 mmol) and treated with cesium carbonate (146 mg, 0.448 mmol). The mixture was stirred at room temperature for 16 hours. The crude material was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.52 (s, 1H), 8.63 (dd, J=8.6, 1.0 Hz, 1H), 8.30 (d, J=8.3 Hz, 1H), 8.27 (dd, J=7.4, 1.3 Hz, 1H), 8.15-8.12 (m, 1H), 7.78 (dd, J=7.0, 1.5 Hz, 1H), 7.77-7.75 (m, OH), 7.72-7.66 (m, 2H), 7.28 (dd, J=8.7, 0.7 Hz, 1H), 6.61 (d, J=8.6 Hz, 1H), 4.05 (dd, J=9.3, 5.8 Hz, 1H), 3.64-3.51 (m, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.26 (ddt, J=13.1, 9.3, 7.4 Hz, 1H), 1.78 (dtd, J=13.3, 7.5, 5.8 Hz, 1H), 0.72 (t, J=7.0 Hz, 3H). MS (APCI+) m/z 474 (M+H)⁺.

Example I-54 4-bromo-N-(naphthalene-1-sulfonyl)-7-[propan-2-yl)oxy]-2,3-dihydro-1H-indene-1-carboxamide

A solution of Example I-53A (40 mg, 0.090 mmol) in N,N-dimethylformamide (0.5 mL) was treated with 2-iodopropane (53.8 μl, 0.538 mmol) and treated with cesium carbonate (146 mg, 0.448 mmol). The mixture was stirred at room temperature for 16 hours. The crude material was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.49 (s, 1H), 8.66 (dd, J=8.7, 1.0 Hz, 1H), 8.34-8.24 (m, 2H), 8.13 (dd, J=8.2, 1.3 Hz, 1H), 7.82-7.72 (m, 1H), 7.72-7.60 (m, 2H), 7.27 (d, J=8.6 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 4.35 (p, J=6.0 Hz, 1H), 4.02 (dd, J=9.5, 5.2 Hz, 1H), 2.75 (t, J=7.5 Hz, 2H), 2.23 (ddt, J=13.2, 9.5, 7.7 Hz, 1H), 1.77 (dtd, J=12.8, 7.2, 5.1 Hz, 1H), 0.91 (d, J=6.1 Hz, 3H), 0.62 (d, J=6.0 Hz, 3H). MS (APCI+) m/z 488 (M+H)⁺.

Example I-55 4-bromo-7-(cyclopropylmethoxy)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A solution of Example I-53A (40 mg, 0.090 mmol) in N,N-dimethylformamide (0.5 mL) was treated with (iodomethyl)cyclopropane (98 mg, 0.538 mmol), treated with cesium carbonate (146 mg, 0.448 mmol), and stirred at room temperature for 16 hours. The crude material was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.52 (s, 1H), 8.64 (dd, J=8.7, 1.1 Hz, 1H), 8.32-8.24 (m, 2H), 8.17-8.09 (m, 1H), 7.77 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.72-7.64 (m, 2H), 7.27 (dd, J=8.7, 0.6 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 4.08 (dd, J=9.4, 5.3 Hz, 1H), 3.45 (dd, J=10.5, 7.1 Hz, 1H), 3.37 (dd, J=10.5, 6.4 Hz, 1H), 2.73 (ddd, J=8.8, 6.6, 2.9 Hz, 2H), 2.26 (dtd, J=13.2, 8.8, 6.7 Hz, 1H), 1.83-1.68 (m, 1H), 0.67-0.51 (m, 1H), 0.31-0.17 (m, 2H), 0.08-−0.03 (m, 2H). MS (APCI+) m/z 500 (M+H)⁺.

Example I-56 8-bromo-5-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Example I-56A 8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

A mixture of Example I-15C, (8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide) (154 mg, 0.542 mmol) in ethylene glycol (˜4 mL) was treated with 85% KOH pellets (400 mg, 6.06 mmol), heated to 220° C. for 4.5 hours, cooled and partitioned between methyl tert-butyl ether (30 mL) and 1 M aqueous HCl (15 mL). The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (30 mL). The combined organic layers were washed with 0.1 M aqueous HCl, washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was chromatographed on silica gel, eluting with a gradient of 10% to 50%[200:1:1 ethyl acetate:HCOOH:H₂O] in heptanes to provide the title compound. ¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ ppm 7.39 (d, J=8.7 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 3.78 (s, 4H), 2.72 (dd, J=5.3, 18.1 Hz, 1H), 2.42 (ddd, J=6.3, 11.5, 17.9 Hz, 1H), 2.17-2.12 (m, 1H), 1.86-1.77 (m, 2H), 1.56-1.46 (m, 1H).

Example I-56B 8-bromo-5-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

To a mixture of Example I-56A (8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid) (56 mg, 0.196 mmol), EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (75 mg, 0.393 mmol) and DMAP (4-dimethylaminopyridine) (26.4 mg, 0.216 mmol) in dichloromethane (1 mL) was added quinoline-5-sulfonamide (45.0 mg, 0.216 mmol). The mixture was stirred at room temperature for 16 hours, and concentrated with a stream of N₂. The residue was diluted with N,N-dimethylformamide and directly purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1% TFA] to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.80 (s, 1H), 9.05-9.02 (m, 2H), 8.32 (d, J=8.5 Hz, 1H), 8.28 (dd, J=1.3, 7.5 Hz, 1H), 7.88 (dd, J=7.4, 8.4 Hz, 1H), 7.78-7.74 (m, 1H), 7.10 (d, J=8.7 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 3.74 (dd, J=2.6, 6.5 Hz, 1H), 3.66 (s, 3H), 2.54-2.45 (m, 1H), 2.23 (ddd, J=6.2, 11.3, 17.7 Hz, 1H), 1.91-1.84 (m, 1H), 1.74 (tdd, J=2.8, 6.5, 13.5 Hz, 1H), 1.53-1.44 (m, 1H), 1.12-0.99 (m, 1H). MS (ESI+) m/z 475, 477 (M+H)⁺.

Example I-57 5-methoxy-8-(4-methylphenyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

p-Tolylboronic acid (12.9 mg, 0.09 mmol, 1.5 equivalents) and PdCl₂(dppf) ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 5% w/w on glass beads 92.6 mg, 0.006 mmol, 0.1 equivalents) were weighed into a 4 mL vial. Example I-15D (30.0 mg, 0.06 mmol, 1.0 equivalent) in dioxane (1 mL) was added, followed by the addition of Cs₂CO₃ (2 M in H₂O, 94 μL, 0.18 mmol, 3.0 equivalents). The reaction was capped and heated to 80° C. for 16 hours. The reaction was filtered, the filtrate was concentrated and the residue was purified using preparative reverse phase HPLC/MS method TFA8. After purification with TFA8 method, the sample was impure and was repurified using preparative reverse phase HPLC/MS method AA8 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.85-8.58 (m, 1H), 8.26-7.90 (m, 3H), 7.72-7.38 (m, 3H), 6.93-6.68 (m, 6H), 3.75 (s, 3H), 3.18 (m, 1H), 2.44 (s, 2H), 2.23 (s, 3H), 2.10-1.95 (m, 2H), 1.32 (d, J=52.4 Hz, 3H). MS (APCI+) m/z 486.0 (M+H)⁺.

Example I-58 4-bromo-7-(difluoromethoxy)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a 50 mL flask was added potassium hydroxide (37.7 mg, 0.672 mmol) in acetonitrile (0.7 mL) and water (0.700 mL). The mixture was stirred at room temperature until the material was in solution. The reaction was cooled to 0° C. and Example I-53A (60 mg, 0.134 mmol) was added slowly. Diethyl (bromodifluoromethyl)phosphonate (0.072 mL, 0.403 mmol) was added dropwise. The mixture was stirred at 0° C. for 10 minutes, and the reaction was allowed to warm to room temperature over 4 hours. Aqueous HCl (1 N, 1 mL) was added and the mixture was extracted with 3×5 mL of ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via a 12 g cartridge eluting with a gradient of 0-6% methanol/dichloromethane over a period of 12 minutes to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.72 (s, 1H), 8.63 (dd, J=8.6, 1.1 Hz, 1H), 8.24 (dd, J=20.3, 7.8 Hz, 2H), 8.11 (d, J=8.1 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.66 (dt, J=15.6, 7.7 Hz, 2H), 7.43 (d, J=8.6 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H), 6.82 (t, J=73.8 Hz, 1H), 4.12 (bs, 1H), 2.82-2.66 (m, 2H), 2.29 (dq, J=16.9, 8.8 Hz, 1H), 1.77 (bs, 1H). MS (APCI+) m/z 496 (M+H⁺).

Example I-59 4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A suspension of Example I-19C (30 mg, 0.065 mmol), copper(I) chloride (112 mg, 1.129 mmol) in dimethyl acetamide (0.5 mL) was purged with nitrogen and heated at 150° C. for 5 hours. The reaction was cooled, filtered, and washed with ethyl acetate. The filtrate was acidified with 0.5 mL 1 N aqueous HCl. Water (3 mL) was added and the mixture was extracted with 3×15 mL of ethyl acetate. The combined organics were concentrated in vacuo and the residue was chromatographed using a 12 g silica gel cartridge with 0-100% ethyl acetate/heptanes over a period of 10 minutes to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.57 (s, 1H), 8.73-8.61 (m, 1H), 8.30 (d, J=8.2 Hz, 1H), 8.26 (dd, J=7.4, 1.3 Hz, 1H), 8.17-8.08 (m, 1H), 7.79 (ddd, J=8.6, 6.9, 1.4 Hz, 1H), 7.75-7.60 (m, 2H), 7.15 (d, J=8.6 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 4.02 (m, 1H), 3.10 (s, 3H), 2.77 (t, J=7.5 Hz, 2H), 2.36-2.20 (m, 1H), 1.83 (ddd, J=13.6, 7.7, 5.8 Hz, 1H). MS (APCI+) m/z 416 (M+H⁺).

Example I-60 (1S)-8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Into a 4 mL vial was weighed 8-bromo-5-methoxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (Example I-15, 115 mg, 0.242 mmol) and Pd(dppf)Cl₂ ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 19.80 mg, 0.024 mmol) in tetrahydrofuran (0.5 mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 1.5 mL, 0.750 mmol) was added. The reaction was heated to 50° C. for 16 hours. The reaction mixture was filtered and was purified using preparative HPLC/MS method TFA8 to afford a racemic mixture. The mixture was separated by chiral preparative SFC chromatography using a CHIRALPAK IC, column size 21×250 mm, 5 micron, serial Number: IC00SALK014-812151, using a concentration of 21.5 mg/mL in methanol at a flow rate of 49 g/minutes CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.74 (dd, J=8.6, 1.0 Hz, 1H), 8.30-8.21 (m, 2H), 8.13 (d, J=8.2 Hz, 1H), 7.89-7.78 (m, 1H), 7.78-7.67 (m, 1H), 7.64 (t, J=7.8 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 3.67 (s, 3H), 2.72-2.55 (m, 1H), 2.51-2.47 (m, 2H), 2.33-2.18 (m, 1H), 2.18-2.03 (m, 1H), 2.03-1.83 (m, 1H), 1.80-1.45 (m, 4H), 1.45-1.30 (m, 1H), 1.30-0.93 (m, 3H). MS (APCI+) m/z 450.0 (M+H)⁺.

Example I-61 (1R)-8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-61 was isolated as the second enantiomer to elute from the preparative SFC separation described in Example I-60. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.74 (dd, J=8.6, 1.0 Hz, 1H), 8.39-8.17 (m, 2H), 8.13 (d, J=8.3 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H), 7.72 (t, J=7.5 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 3.67 (s, 3H), 2.65-2.58 (m, 1H), 2.51-2.44 (m, 2H), 2.33-2.21 (m, 1H), 2.17-2.06 (m, 1H), 2.01-1.88 (m, 1H), 1.79-1.33 (m, 5H), 1.30-0.96 (m, 3H). MS (APCI+) m/z 450.0 (M+H)⁺.

Example I-62 (1S)-5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

The material from Example I-50 was separated by Supercritical Fluid Chromatography (SFC) using a 21×250 mm Chiralpak IC chiral column eluting with 30% methanol in liquid CO₂ to provide the title compound as the first peak to elute from the column. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.62 (s, 1H), 9.09 (s, 2H), 8.34 (d, J=8.5 Hz, 1H), 8.30 (dd, J=1.2, 7.4 Hz, 1H), 7.92 (dd, J=7.4, 8.4 Hz, 1H), 7.83 (dd, J=4.3, 8.6 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.56 (d, J=8.8 Hz, 1H), 3.70-3.66 (m, 1H), 3.00 (s, 3H), 2.57-2.37 (m, 2H), 1.83-1.64 (m, 2H), 1.56-1.45 (m, 1H), 1.39-1.29 (m, 1H). MS (ESI+) m/z 475,477 (M+H)⁺.

Example I-63 (1R)-5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

The material from Example I-50 was separated by Supercritical Fluid Chromatography (SFC) using a 21×250 mm Chiralpak IC chiral column eluting with 30% methanol in liquid CO₂ to provide the title compound as the second peak to elute from the column. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.62 (s, 1H), 9.10-9.05 (m, 2H), 8.34 (d, J=8.4 Hz, 1H), 8.30 (dd, J=1.2, 7.5 Hz, 1H), 7.92 (dd, J=7.5, 8.4 Hz, 1H), 7.83 (dd, J=4.3, 8.6 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.56 (d, J=8.8 Hz, 1H), 3.68 (t, J=5.6 Hz, 1H), 3.00 (s, 3H), 2.57-2.38 (m, 2H), 1.83-1.66 (m, 2H), 1.55-1.46 (m, 1H), 1.40-1.29 (m, 1H). MS (ESI+) m/z 475,477 (M+H)⁺.

Example I-64 (1S)-8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-34C (120 mg) was separated by chiral preparative SFC chromatography using a CHIRALPAK IC, column size 21×250 mm, 5 micron, serial Number: IC00SALK014-812151, using a concentration of 25 mg/mL in methanol/dichloromethane 1:1 at a flow rate of 48 g/minutes CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, Chloroform-d) δ ppm 8.57 (dd, J=7.4, 1.2 Hz, 1H), 8.39 (dd, J=7.9, 1.7 Hz, 1H), 8.16 (dd, J=8.1, 1.2 Hz, 1H), 8.01-7.96 (m, 1H), 7.89 (s, 1H), 7.68-7.58 (m, 3H), 7.14 (t, J=7.7 Hz, 1H), 7.10 (dd, J=7.6, 1.4 Hz, 1H), 7.01 (dd, J=7.7, 1.5 Hz, 1H), 2.85 (dt, J=16.4, 5.4 Hz, 1H), 2.74 (ddd, J=16.3, 8.9, 5.0 Hz, 1H), 2.33 (dq, J=15.2, 7.6 Hz, 1H), 1.97 (ddd, J=14.0, 10.3, 3.7 Hz, 1H), 1.92-1.69 (m, 4H), 0.56 (t, J=7.5 Hz, 3H). MS (ESI+) m/z 428 (M+H⁺). R_(T) (chiral SFC)=3.0 minutes. The absolute structure of the title compound was determined by X-ray crystallography.

Example I-65 (1R)-8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Example I-34C (120 mg) was separated by chiral preparative SFC chromatography using a CHIRALPAK IC, column size 21×250 mm, 5 micron, serial Number: IC00SALK014-812151, using a concentration of 25 mg/mL in methanol/dichloromethane 1:1 at a flow rate of 48 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, Chloroform-d) δ ppm 8.57 (dd, J=7.4, 1.2 Hz, 1H), 8.39 (dd, J=7.9, 1.7 Hz, 1H), 8.16 (dd, J=8.3, 1.2 Hz, 1H), 8.02-7.97 (m, 1H), 7.89 (s, 1H), 7.70-7.57 (m, 3H), 7.14 (t, J=7.7 Hz, 1H), 7.10 (dd, J=7.6, 1.4 Hz, 1H), 7.01 (dd, J=7.7, 1.5 Hz, 1H), 2.85 (dt, J=16.4, 5.4 Hz, 1H), 2.74 (ddd, J=16.3, 8.9, 5.0 Hz, 1H), 2.33 (dq, J=15.2, 7.6 Hz, 1H), 1.97 (ddd, J=14.0, 10.3, 3.7 Hz, 1H), 1.92-1.69 (m, 4H), 0.56 (t, J=7.5 Hz, 3H). MS (ESI+) m/z 428 (M+H⁺). R_(T) (chiral SFC)=5.0 minutes.

Example I-66 4-chloro-1-ethyl-N-(1-methyl-1H-indole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-66A 1-methyl-1H-indole-7-sulfonamide

Into a 4 mL vial was added 2 mL concentrated NH₄OH. 1-Methyl-1H-indole-7-sulfonyl chloride (104 mg, 0.45 mmol) in 1 mL tetrahydrofuran was added to the vigorously stirred concentrated NH₄OH. The reaction was stirred for 2 hours, concentrated under a stream of nitrogen, and dried in a vacuum oven to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 7.77 (dd, J=7.9, 1.1 Hz, 1H), 7.66 (dd, J=7.6, 1.1 Hz, 1H), 7.39 (d, J=3.2 Hz, 1H), 7.09 (t, J=7.7 Hz, 1H), 6.58 (d, J=3.1 Hz, 1H), 4.10 (s, 3H).

Example I-66B 4-chloro-1-ethyl-N-(1-methyl-1H-indole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

1-Methyl-1H-indole-7-sulfonamide (22.46 mg, 0.11 mmol, 1.2 equivalents) was weighed into a 4 mL vial. Example I-17A (20.0 mg, 0.09 mmol, 1.0 equivalent), EDC HCl ((1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 34.0 mg, 0.18 mmol, 2.0 equivalents) and DMAP (4-dimethylaminopyridine) (11.9 mg, 0.10 mmol, 1.1 equivalents) were dissolved in dichloromethane (0.5 mL) and was added to the vial containing 1-methyl-1H-indole-7-sulfonamide. The reaction was stirred overnight at room temperature. The solvent was removed under a stream of nitrogen and the residue was reconstituted in methanol and was purified using preparative reverse phase HPLC/MS method TFA6 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 7.90 (dd, J=7.9, 1.2 Hz, 1H), 7.77 (dd, J=7.8, 1.2 Hz, 1H), 7.37 (d, J=3.2 Hz, 1H), 7.31-7.23 (m, 1H), 7.23-7.11 (m, 3H), 6.64 (d, J=3.2 Hz, 1H), 4.00 (s, 3H), 2.85 (t, J=7.3 Hz, 2H), 2.52-2.40 (m, 1H), 2.12-1.97 (m, 2H), 1.80-1.66 (m, 1H), 0.65 (t, J=7.3 Hz, 3H). MS (APCI+) m/z 417.1 (M+H)⁺.

Example I-67 5-methoxy-8-(2-methylpropyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

In a 4 mL vial was weighed Example I-15D (25 mg, 0.05 mmol, 1.0 equivalent) and Pd(dppf)Cl₂ ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 3.86 mg, 0.005 mmol, 0.1 equivalents) in tetrahydrofuran (0.5 mL). Isobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.32 mL, 0.750 mmol) was added. The reaction was heated to 50° C. for 16 hours. The sample was directly purified using preparative reverse phase HPLC/MS method TFA8 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.67 (d, J=8.7 Hz, 1H), 8.33-8.21 (m, 2H), 8.13 (d, J=8.1 Hz, 1H), 7.84-7.75 (m, 1H), 7.75-7.61 (m, 2H), 6.73 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 3.81 (dd, J=6.0, 2.6 Hz, 1H), 3.67 (s, 3H), 2.50-2.44 (m, 1H), 2.33-2.19 (m, 1H), 1.95-1.76 (m, 2H), 1.75-1.60 (m, 2H), 1.51-1.36 (m, 2H), 1.08-1.00 (m, 1H), 0.59 (d, J=6.6 Hz, 3H), 0.48 (d, J=6.4 Hz, 3H). MS (APCI+) m/z 452.1 (M+H)⁺.

Example I-68 8-methoxy-5-(2-methylpropyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Into a 4 mL vial was weighed Example I-15D (25 mg, 0.05 mmol, 1.0 equivalent) and PEPPSI IPentCl ([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II)) (4.53 mg, 0.005 mmol, 0.1 equivalents) in tetrahydrofuran (0.5 mL). Isobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.32 mL, 0.750 mmol) was added. The reaction was stirred for 16 hours at room temperature. The sample was directly purified using preparative reverse phase HPLC/MS method TFA8 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.69 (d, J=8.7 Hz, 1H), 8.33-8.21 (m, 2H), 8.18-8.10 (m, 1H), 7.87-7.78 (m, 1H), 7.77-7.63 (m, 2H), 6.84 (d, J=8.3 Hz, 1H), 6.47 (d, J=8.3 Hz, 1H), 3.73-3.65 (m, 1H), 2.90 (s, 3H), 2.54-2.36 (m, 2H), 2.27 (d, J=7.0 Hz, 2H), 1.87-1.73 (m, 1H), 1.70-1.57 (m, 2H), 1.52-1.32 (m, 2H), 0.85-0.77 (m, 6H). MS (APCI+) m/z 452.1 (M+H)⁺.

Example I-69 5-cyclobutyl-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Into a 4 mL vial was weighed Example I-15D (25 mg, 0.05 mmol, 1.0 equivalent) and PEPPSI IPentCl ([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II)) 4.53 mg, 0.005 mmol, 0.1 equivalents) in tetrahydrofuran (0.5 mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.32 mL, 0.750 mmol) was added. The reaction was stirred for 16 hours at room temperature. The sample was directly purified using preparative reverse phase HPLC/MS method TFA8 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.73-8.65 (m, 1H), 8.32-8.21 (m, 2H), 8.14 (d, J=8.2 Hz, 1H), 7.82 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.77-7.62 (m, 2H), 6.96 (d, J=8.4 Hz, 1H), 6.51 (d, J=8.4 Hz, 1H), 3.71-3.63 (m, 1H), 3.41 (p, J=9.1, 8.6 Hz, 1H), 2.91 (s, 3H), 2.47-2.28 (m, 2H), 2.25-2.12 (m, 2H), 1.99-1.81 (m, 3H), 1.81-1.60 (m, 3H), 1.49-1.25 (m, 2H). MS (APCI+) m/z 450.0 (M+H)⁺.

Example I-70 5-chloro-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Example I-70A 8-hydroxy-3,4-dihydronaphthalen-1(2H)-one

Naphthalene-1,8-diol (10 g, 62 mmol) (CAS#569-42-6) and ethanol (10 mL) were added to 10% Pd/C, dry (0.518 g, 0.487 mmol) in a 250 mL SS pressure bottle under argon. The mixture was shaken for 24 hours at 60 psi hydrogen at 60° C. and another 24 hours at room temperature at 60 psi hydrogen. The mixture was concentrated, and filtered through silica with 10% methyl tert-butyl ether/heptanes to provide the crude title compound which was used without further purification.

Example I-70B 8-methoxy-3,4-dihydronaphthalen-1(2H)-one

Potassium hydroxide (3.65 g, 65 mmol) was ground in a mortar, transferred to a round-bottomed flask and heated in dimethyl sulfoxide (65 mL) at 60° C. for about 15 minutes. The mixture was cooled to near 0° C., placed under a stream of nitrogen, and treated with Example I-70A (8.11 g, 17 mmol) in dimethyl sulfoxide (10 mL) with a dimethyl sulfoxide (5 mL) rinse. The reaction flask was removed from the bath and the mixture was stirred 40 minutes before the flask was placed back into the ice water bath. Iodomethane (3.4 mL, 55 mmol) was added dropwise, the flask was again removed from the bath and the reaction mixture was stirred at room temperature for 30 minutes before the contents were poured into ice water (400 mL). The mixture was extracted with 1:1 methyl tert-butyl ether/heptane (2×200 mL). The combined extracts were washed with brine, dried (Na₂SO₄), filtered, concentrated and chromatographed on silica (20 to 80% methyl tert-butyl ether/heptane) to give crude material which was chromatographed on silica (0 to 10% ethyl acetate/dichloromethane) to give the title compound. MS (ESI+) m/z=177 (M+H)⁺.

Example I-70C 8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde

To a suspension of methoxymethyl)triphenylphosphonium chloride (1.40 g, 4.08 mmol) in anhydrous tetrahydrofuran (6.0 mL) under nitrogen and at room temperature was added 1 M potassium tert-butoxide (4.0 mL, 4.0 mmol) dropwise. The resulting reaction mixture was stirred for 20 minutes before a solution of the Example I-70B (599 mg, 3.40 mmol) in tetrahydrofuran (5.0 mL) was added dropwise over 7 minutes. The resulting reaction mixture was stirred 40 minutes. Aqueous HCl (3 M, 5.0 mL) was added and stirring at room temperature was continued for 16 hours. The reaction mixture was concentrated and the mixture was extracted with 3×50 mL of methyl tert-butyl ether. The combined organic phases were washed with dilute hydrochloric acid and with brine, dried (Na₂SO₄), filtered, concentrated and chromatographed on silica (20 to 60% CHCl₃/heptane) to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.60 (d, J=1.9 Hz, 1H), 7.18 (dd, J=8.2, 7.7 Hz, 1H), 6.79-6.76 (m, 1H), 6.74 (d, J=8.2 Hz, 1H), 3.80 (s, 3H), 3.79-3.75 (m, 1H), 2.81-2.69 (m, 2H), 2.20-2.12 (m, 1H), 1.87-1.64 (m, 3H). MS (ESI+) m/z 191 (M+H)⁺.

Example I-70D 8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

To a solution of Example 70C (38 mg, 0.20 mmol) in acetone (2.0 mL) at 0° C. was added dropwise a 2.0 M solution of chromium trioxide in aqueous sulfuric acid (440 μL, 0.88 mmol) over six minutes. The cold solution was for stirred 30 minutes, removed from the bath and after 10 minutes quenched with isopropanol (220 μL). After two minutes, the suspension was filtered through diatomaceous earth with a thorough ethyl acetate rinse. The filtrate was concentrated and chromatographed on silica (67% to 100% methyl tert-butyl ether/heptane) to give the crude product which was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 10 to 60% gradient of acetonitrile in 0.1% aqueous TFA] to give the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.95 (s, 1H), 7.11 (dd, J=8.2, 7.7 Hz, 1H), 6.74 (dd, J=8.2, 1.0 Hz, 1H), 6.69 (dd, J=7.7, 1.0 Hz, 1H), 3.71 (s, 3H), 3.65 (dd, J=6.5, 4.8 Hz, 1H), 2.75-2.61 (m, 2H), 2.01-1.86 (m, 2H), 1.71-1.64 (m, 2H). MS (ESI+) m/z 229 (M+Na)⁺.

Example I-70E 5-chloro-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

To a solution of Example I-70D (26 mg, 0.14 mmol) in anhydrous dichloromethane (500 μL) at 0° C. was carefully added sulfuryl chloride (15.5 μL, 0.19 mmol). The resulting solution was stirred cold about 15 minutes and another 90 minutes at room temperature. The suspension was cooled back towards 0° C., quenched with 0.5 M aqueous Na₂S₂O₃ (0.2 mL), stirred another ten minutes, diluted with brine (0.2 mL) and extracted thrice with methyl tert-butyl ether. The combined extracts were dried (Na₂SO₄), filtered, concentrated and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 10 to 60% gradient of acetonitrile in 0.1% aqueous TFA] to give the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.14 (s, 1H), 7.29 (d, J=8.7 Hz, 1H), 6.84 (d, J=8.7 Hz, 1H), 3.73 (s, 3H), 3.71 (dd, J=6.5, 4.0 Hz, 1H), 2.73 (ddd, J=17.6, 5.2, 4.7 Hz, 1H), 2.56 (ddd, J=17.6, 9.8, 5.8 Hz, 1H), 2.04-1.97 (m, 1H), 1.89-1.73 (m, 2H), 1.70-1.60 (m, 1H). MS (ESI+) m/z=241 (M+H)⁺.

Example I-70F 5-chloro-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

To a solution of Example I-70E (21 mg, 87 μmol, EDAC (1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 33 mg, 0.17 mmol) and DMAP (4-dimethylaminopyridine) (12 mg, 98 μmol in anhydrous dichloromethane (250 μL) was added naphthalene-1-sulfonamide (21 mg, 0.10 mmol). The solution was stirred for 90 minutes, concentrated and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 80% gradient of acetonitrile in 0.1% aqueous TFA] to give the title compound. ¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ ppm 12.54 (s, 1H), 8.69 (dd, J=8.6, 1.1 Hz, 1H), 8.31-8.28 (m, 1H), 8.24 (dd, J=7.4, 1.3 Hz, 1H), 8.16-8.13 (m, 1H), 7.82 (ddd, J=8.6, 6.9, 1.4 Hz, 1H), 7.72 (ddd, J=8.1, 6.9, 1.1 Hz, 1H), 7.67 (dd, J=8.2, 7.4 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 3.72-3.68 (m, 1H), 2.94 (s, 3H), 2.58-2.51 (m, 1H), 2.44 (ddd, J=17.4, 9.0, 5.6 Hz, 1H), 1.83-1.74 (m, 1H), 1.74-1.67 (m, 1H), 1.53-1.45 (m, 1H), 1.37-1.27 (m, 1H). MS (ESI+) m/z=430 (M+H)⁺.

Example I-71 (1S)-4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-59 (60 mg) was separated by chiral preparative SFC chromatography using a CHIRALPAK IC, column size 21×250 mm, 5 micron, serial Number: IC00SALK014-812151, using a concentration of 5.9 mg/mL in methanol/dichloromethane 1:1 at a flow rate of 49 g/minutes CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.57 (s, 1H), 8.65 (dd, J=8.6, 1.1 Hz, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.25 (dd, J=7.4, 1.2 Hz, 1H), 8.14 (dd, J=8.2, 1.3 Hz, 1H), 7.79 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.64 (m, 2H), 7.15 (d, J=8.6 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 4.01 (dd, J=9.2, 5.6 Hz, 1H), 3.11 (s, 3H), 2.77 (t, J=7.5 Hz, 2H), 2.36-2.22 (m, 1H), 1.90-1.74 (m, 1H). MS (APCI+) m/z 416 (M+H⁺). R_(T) (chiral SFC)=5.4 minutes.

Example I-72 (1R)-4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-59 (60 mg) was separated by chiral preparative SFC chromatography using a CHIRALPAK IC, column size 21×250 mm, 5 micron, serial Number: IC00SALK014-812151, using a concentration of 5.9 mg/mL in methanol/dichloromethane 1:1 at a flow rate of 49 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.57 (s, 1H), 8.65 (dd, J=8.6, 1.1 Hz, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.25 (dd, J=7.4, 1.2 Hz, 1H), 8.14 (dd, J=8.2, 1.3 Hz, 1H), 7.79 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.64 (m, 2H), 7.15 (d, J=8.6 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 4.01 (dd, J=9.2, 5.6 Hz, 1H), 3.11 (s, 3H), 2.77 (t, J=7.5 Hz, 2H), 2.36-2.22 (m, 1H), 1.90-1.74 (m, 1H). MS (APCI+) m/z 416 (M+H)⁺. R_(T) (chiral SFC)=6.3 minutes.

Example I-73 5,8-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Example I-73A 5,8-dimethoxy-3,4-dihydronaphthalene-1-carbonitrile

A flask containing 1.6 M n-butyllithium in hexanes (4.66 mL, 7.46 mmol) was cooled to −78° C. under N₂ and treated dropwise with a solution of trimethylsilyl cyanide (1 mL, 7.46 mmol) in tetrahydrofuran (5 mL). The mixture was allowed to warm to room temperature and was stirred for 1 hour. The mixture was diluted with heptanes and the material was collected by filtration to provide a material which contained LiCN. A solution of 5,8-dimethoxy-3,4-dihydronaphthalen-1(2H)-one (CAS#1015-55-0) (0.153 g, 0.742 mmol) in N,N-dimethylformamide (1 mL) was cooled to 0° C., treated with diethyl cyanophosphonate (0.225 mL, 1.484 mmol), treated with 20 mg of the LiCN containing material from above, stirred at room temperature for 90 minutes, treated with an additional 20 mg of the LiCN containing material from above and stirred at room temperature for 3 days. The mixture was partitioned between methyl tert-butyl ether (30 mL) and water. The methyl tert-butyl ether layer was washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was dissolved in toluene (˜5 mL), treated with para-toluenesulfonic acid monohydrate (0.014 g, 0.074 mmol) and heated to 120° C. for 3 hours. The mixture was cooled, diluted with methyl tert-butyl ether (30 mL), washed with aqueous NaHCO₃ solution (10 mL), washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was chromatographed on silica gel, eluting with a gradient of 10% to 30% (over 9 minutes) ethyl acetate in heptanes to provide the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 6.95 (t, J=5.1 Hz, 1H), 6.83 (d, J=9.0 Hz, 1H), 6.76 (d, J=9.0 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 2.76 (t, J=8.1 Hz, 2H), 2.38-2.33 (m, 2H).

Example I-73B 5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile

A solution of Example I-73A (5,8-dimethoxy-3,4-dihydronaphthalene-1-carbonitrile) (0.16 g, 0.743 mmol) in ethanol (10 mL) was treated with NaBH₄ (0.169 g, 4.46 mmol), heated to 80° C. for 20 minutes, cooled and partitioned between methyl tert-butyl ether (˜50 mL) and 1 M aqueous HCl (˜25 mL). The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (˜25 mL). The combined methyl tert-butyl ether layers were concentrated to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 6.74 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.9 Hz, 1H), 4.10-4.07 (m, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 2.93-2.85 (m, 1H), 2.47 (ddd, J=6.3, 11.1, 17.8 Hz, 1H), 2.29-2.22 (m, 1H), 2.04-1.86 (m, 2H), 1.80 (tdd, J=3.0, 5.4, 12.7 Hz, 1H).

Example I-73C 5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

A solution of Example I-73B (5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile) (0.132 g, 0.608 mmol) in ethylene glycol (10 mL) was treated with 45% w/v KOH in water (5 mL, 44.1 mmol), heated to 170° C. for 16 hours, heated for an additional 8 hours, cooled and partitioned between methyl tert-butyl ether (75 mL) and 1 M aqueous HCl (75 mL). The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (˜50 mL). The combined methyl tert-butyl ether layers were washed with 0.1 M aqueous HCl (˜25 mL), washed with brine, dried (MgSO₄), filtered, and concentrated to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 6.71 (d, J=8.8 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 3.88 (t, J=5.7 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 2.77 (dt, J=5.4, 17.7 Hz, 1H), 2.57 (ddd, J=6.2, 8.7, 17.7 Hz, 1H), 2.18-2.10 (m, 1H), 1.96 (dddd, J=3.4, 6.4, 9.9, 13.2 Hz, 1H), 1.89-1.72 (m, 2H).

Example I-73D 5,8-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

To a solution of Example I-73C (5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid) (20.5 mg, 0.087 mmol), EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (33.3 mg, 0.174 mmol) and DMAP (4-dimethylaminopyridine) (11.66 mg, 0.095 mmol) in dichloromethane (1 mL) was added naphthalene-1-sulfonamide (19.78 mg, 0.095 mmol). The mixture was stirred at room temperature for 16 hours, concentrated with a stream of N₂, diluted with N,N-dimethylformamide and directly purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1% TFA] to afford the title compound. ¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ ppm 12.45 (s, 1H), 8.69 (dd, J=1.0, 8.7 Hz, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.24 (dd, J=1.2, 7.4 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.81 (ddd, J=1.4, 6.9, 8.5 Hz, 1H), 7.71 (ddd, J=1.1, 6.8, 8.1 Hz, 1H), 7.66 (dd, J=7.4, 8.2 Hz, 1H), 6.64 (d, J=8.9 Hz, 1H), 6.47 (d, J=8.9 Hz, 1H), 3.66 (t, J=5.8 Hz, 1H), 3.64 (s, 3H), 2.89 (s, 3H), 2.43 (dt, J=5.4, 17.5 Hz, 1H), 2.32 (ddd, J=5.7, 9.0, 17.5 Hz, 1H), 1.79-1.71 (m, 1H), 1.68-1.62 (m, 1H), 1.45-1.37 (m, 1H), 1.34-1.25 (m, 1H). MS (ESI+) m/z 426 (M+H)⁺.

Example I-74 4-chloro-1-ethyl-N-(1-methyl-1H-indole-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-17A (25.0 mg, 0.11 mmol, 1.0 equivalent), EDC HCl (1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 42.3 mg, 0.22 mmol, 2.0 equivalents) and DMAP (4-dimethylaminopyridine) (14.95 mg, 0.12, mmol, 1.1 equivalents) were dissolved in CH₂Cl₂ (1.0 mL) and added to a vial containing 1-methyl-1H-indole-4-sulfonamide (28.1 mg, 0.13 mmol, 1.2 equivalents). The reaction was stirred for 16 hours at room temperature. The solvent was removed under a stream of N₂, dissolved in dimethyl sulfoxide, and purified using preparative reverse phase HPLC/MS method TFA8 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 7.63 (d, J=8.1 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.35 (d, J=2.9 Hz, 1H), 7.21 (t, J=7.9 Hz, 1H), 7.17-7.12 (m, 2H), 7.11-7.04 (m, 1H), 6.78 (dd, J=3.1, 0.9 Hz, 1H), 3.80 (s, 3H), 2.78 (t, J=7.4 Hz, 2H), 2.50-2.38 (m, 1H), 2.01-1.87 (m, 2H), 1.75-1.61 (m, 1H), 0.61 (t, J=7.4 Hz, 3H). MS (APCI+) m/z 417.0 (M+H)⁺.

Example I-75 7-methoxy-4-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A solution of Example I-19C (35 mg, 0.076 mmol), potassium carbonate (42.0 mg, 0.304 mmol), trimethylboroxine (0.043 mL, 0.304 mmol) in 1,4-dioxane (0.7 mL) and water (0.12 mL) was degassed with bubbling nitrogen. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (24.84 mg, 0.030 mmol) was added and the mixture was heated at 90° C. with stirring for 16 hours. The reaction was quenched with water (1 mL), acidified with 1 N aqueous HCl (0.1 mL), and extracted with dichloromethane (2 mL). The layers were separated, the solvent was evaporated in vacuo and the resulting residue was chromatographed using a 12 g silica gel cartridge with 0-100% ethyl acetate/heptanes over a period of 10 minutes to give crude product (12 mg) which was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.47 (s, 1H), 8.67 (dd, J=8.6, 1.0 Hz, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.26 (dd, J=7.4, 1.2 Hz, 1H), 8.13 (dt, J=8.2, 0.9 Hz, 1H), 7.85-7.77 (m, 1H), 7.74-7.64 (m, 2H), 6.88 (d, J=8.2 Hz, 1H), 6.48 (d, J=8.2 Hz, 1H), 3.95 (dd, J=9.1, 5.6 Hz, 1H), 3.08 (s, 3H), 2.66 (td, J=7.3, 3.2 Hz, 2H), 2.27-2.13 (m, 1H), 2.05 (s, 3H), 1.85-1.72 (m, 1H). MS (APCI+) m/z 396 (M+H⁺).

Example I-76 4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was added Example I-19C (100 mg, 0.217 mmol) and PEPPSI IPentCl ([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II)) (17.74 mg, 0.022 mmol) in tetrahydrofuran (0.5 mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.869 mL, 0.434 mmol) was added. The reaction was stirred for 16 hours at room temperature. The sample was directly purified using preparative HPLC/MS method TFA8 to afford the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.68 (d, J=8.7 Hz, 1H), 8.39-8.31 (m, 1H), 8.29 (dd, J=7.4, 1.3 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.84 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.79-7.68 (m, 2H), 7.02 (d, J=8.3 Hz, 1H), 6.59 (d, J=8.3 Hz, 1H), 3.95 (dd, J=9.1, 5.5 Hz, 1H), 3.40 (p, J=8.6 Hz, 1H), 3.13 (s, 3H), 2.69 (t, J=7.6 Hz, 2H), 2.31-2.16 (m, 3H), 2.04-1.86 (m, 3H), 1.86-1.67 (m, 2H). MS (APCI+) m/z 436.1 (M+H)⁺.

Example I-77 4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was added Example I-44 (30 mg, 0.065 mmol) and PEPPSI IPentCl ([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II)) (5.31 mg, 6.50 μmol) in tetrahydrofuran (0.5 mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.520 mL, 0.260 mmol) was added. The reaction was stirred for 16 hours at room temperature. The sample was directly purified using preparative HPLC/MS method TFA8 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 9.12 (dd, J=4.2, 1.6 Hz, 1H), 9.11-9.04 (m, 1H), 8.45-8.35 (m, 2H), 7.99 (dd, J=8.5, 7.5 Hz, 1H), 7.87 (dd, J=8.8, 4.2 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 3.94 (dd, J=9.1, 5.8 Hz, 1H), 3.47-3.34 (m, 1H), 3.12 (s, 3H), 2.71 (s, 2H), 2.35-2.16 (m, 3H), 2.05-1.91 (m, 3H), 1.91-1.72 (m, 2H). MS (APCI+) m/z 437.1 (M+H)⁺.

Example I-78 4-bromo-N-(imidazo[1,2-a]pyridine-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide Example I-78A imidazo[1,2-a]pyridine-5-sulfonamide

Di-n-butylmagnesium (2.74 mL, 2.74 mmol, 1 M in tetrahydrofuran) and n-butyllithium (0.365 mL, 0.914 mmol, 2.5 M in hexanes) were combined. The mixture was cooled (ice/acetone bath at −10° C.) and 3 mL of tetrahydrofuran was added. A solution of 5-bromoimidazo[1,2-a]pyridine (0.450 g, 2.284 mmol) (CAS#69214-09-1) in tetrahydrofuran (9 mL) was added dropwise. The reaction was stirred at −10° C. for a total of 2 hours. The cold mixture was added to a cooled solution of sulfuryl chloride (0.426 mL, 5.25 mmol) in tetrahydrofuran (3 mL) while stirring in a dry ice/acetone bath keeping the internal temperature below −10° C. The cold bath was removed and the reaction was allowed to warm up to room temperature. The crude sulfonyl chloride suspension was filtered and the material was added to a rapidly stirring solution of ammonium hydroxide. The solvent was reduced and the crude material was filtered. The material was filtered, washed with water, and dried under reduced pressure to provide the title compound. ¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ ppm 8.31-8.15 (m, 2H), 7.90 (d, J=9.0 Hz, 1H), 7.83 (d, J=1.3 Hz, 1H), 7.56 (dd, J=7.1, 1.1 Hz, 1H), 7.49-7.39 (m, 1H), 7.19-7.08 (m, 1H).

Example I-78B 4-bromo-N-(imidazo[1,2-a]pyridine-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide

Example I-19B (50 mg, 0.184 mmol), N,N-dimethylpyridin-4-amine (24.78 mg, 0.203 mmol), and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (70.7 mg, 0.369 mmol) were combined in N,N-dimethylacetamide (1 mL). After 30 minutes, Example I-78A (41 mg, 0.208 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction was quenched with 0.5 mL of water and 10 drops of 1 M aqueous HCl, and put through an aqueous/organic extractor tube with dichloromethane (2×1 mL). The solvent was removed and the crude material was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide crude title compound. The crude material was triturated with 0.5 mL of dichloromethane and the solvent was removed to provide the title compound as a trifluoroacetic acid salt. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 8.34 (dd, J=1.8, 0.8 Hz, 1H), 8.12 (d, J=1.7 Hz, 1H), 8.05 (dt, J=9.0, 1.0 Hz, 1H), 7.82 (dd, J=7.3, 1.1 Hz, 1H), 7.73 (dd, J=9.0, 7.2 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 3.94 (dd, J=9.2, 5.3 Hz, 1H), 3.30 (s, 3H), 2.79 (qdd, J=16.0, 8.7, 6.0 Hz, 2H), 2.29 (dtd, J=13.1, 9.0, 6.5 Hz, 1H), 1.92 (ddt, J=13.0, 8.8, 5.6 Hz, 1H). MS (APCI+) 451 m/z (M+H)⁺.

Example I-79 2-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide Example I-79A 2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid

A solution of Example I-102K (2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile) (0.63 g, 2.65 mmol) in ethanol (10.58 mL) was treated with a solution of potassium hydroxide (0.742 g, 13.23 mmol) in water (2.65 mL). The mixture was heated at 80° C. for 5 hours, cooled to 0° C., and acidified with 6 M aqueous HCl to pH ˜2. The resulting precipitate was collected by filtration, washed with water, and dried in a vacuum oven provide the title compound. ¹H NMR (400 MHz, CDCL₃) δ ppm 7.28 (d, J=8.9 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H), 4.32 (dd, J=2.6, 5.6 Hz, 1H), 3.84 (s, 3H), 3.44 (dd, J=5.6, 14.2 Hz, 1H), 3.33 (dd, J=2.6, 14.2 Hz, 1H).

Example I-79B 2-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

A solution of Example I-79A (2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid) (12 mg, 0.047 mmol) in dichloromethane was treated with oxalyl chloride (20.43 μl, 0.233 mmol), treated with a catalytic amount of N,N-dimethylformamide, stirred at room temperature for ˜30 minutes and concentrated with a stream of N₂. The residue was dissolved in dichloromethane (˜0.3 mL) and added to a 0° C. solution of naphthalene-1-sulfonamide (12.58 mg, 0.061 mmol), triethylamine (13.01 μl, 0.093 mmol) and DMAP (4-dimethylaminopyridine) (0.570 mg, 4.67 μmol) in dichloromethane (˜0.2 mL). The mixture was stirred for 2 hours, and concentrated with a stream of N₂. The residue was dissolved in N,N-dimethylformamide (˜1 mL) and was directly purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1% TFA] to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.87 (s, 1H), 8.61 (d, J=8.7 Hz, 1H), 8.33-8.28 (m, 2H), 8.14 (d, J=8.0 Hz, 1H), 7.79 (ddd, J=1.5, 6.9, 8.6 Hz, 1H), 7.74-7.67 (m, 2H), 7.23 (d, J=8.9 Hz, 1H), 6.60 (d, J=8.9 Hz, 1H), 4.38 (dd, J=2.4, 5.7 Hz, 1H), 3.34 (s, 3H), 3.25 (dd, J=6.3, 7.9 Hz, 1H), 2.69 (dd, J=2.5, 14.2 Hz, 1H). MS (ESI+) m/z 446,448 (M+H)⁺.

Example I-80 (1S)-4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was weighed Example I-19 (100 mg, 0.217 mmol) and PEPPSI IPentCl ([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II)) (17.74 mg, 0.022 mmol) in tetrahydrofuran (0.5 mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.869 mL, 0.434 mmol) was added. The reaction was stirred for 16 hours at room temperature, and directly purified using preparative reverse phase HPLC/MS method TFA8 to afford the racemate of the title compound. The racemate was separated by chiral preparative SFC chromatography using a CHIRALPAK AD-H, column size 21×250 mm, 5 micron, serial Number: ADH0SAMA003-810291, using a concentration of 12 mg/mL in methanol at a flow rate of 48 g/minutes CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.66 (d, J=8.6 Hz, 1H), 8.32-8.23 (m, 2H), 8.14 (d, J=8.2 Hz, 1H), 7.84-7.76 (m, 1H), 7.76-7.65 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 3.92 (dd, J=9.1, 5.6 Hz, 1H), 3.37 (p, J=8.7 Hz, 1H), 3.11 (s, 3H), 2.73-2.59 (m, 2H), 2.28-2.14 (m, 3H), 2.01-1.84 (m, 3H), 1.82-1.68 (m, 2H). MS (APCI+) m/z 436.1 (M+H)⁺.

Example I-81 (1R)-4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-81 was isolated as the second enantiomer during the preparative SFC separation described in Example I-80. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.67 (d, J=8.5 Hz, 1H), 8.20-8.15 (m, 2H), 8.06 (d, J=8.0 Hz, 1H), 7.76-7.50 (m, 3H), 6.96 (d, J=8.3 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 3.88-3.77 (m, 1H), 3.35 (q, J=8.9 Hz, 1H), 3.18 (s, 3H), 2.64 (q, J=7.9 Hz, 2H), 2.23-2.09 (m, 3H), 2.02-1.65 (m, 5H). MS (APCI+) m/z 436.1 (M+H)⁺.

Example I-82 8-cyclobutyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Into a 4 mL vial was added 8-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (68 mg, 0.323 mmol) and PEPPSI IPentCl ([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II)) (27.8 mg, 0.032 mmol) in tetrahydrofuran (1 mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 2.58 mL, 1.291 mmol) was added. The reaction was heated at 50° C. for 16 hours. The reaction was purified using preparative reverse phase HPLC/MS method TFA1 to provide 8-cyclobutyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid. Into a 4 mL vial was added 8-cyclobutyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (24 mg, 0.104 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (40.0 mg, 0.208 mmol), and N,N-dimethylpyridin-4-amine (14.00 mg, 0.115 mmol) in dichloromethane (0.5 mL). Naphthalene-1-sulfonamide (23.76 mg, 0.115 mmol) was added. The reaction was stirred for 16 hours at room temperature. The solvent was removed under a stream of N₂ and the residue was redissolved in methanol. The reaction was purified using preparative reverse phase HPLC/MS method TFA8 to afford the title compound. ¹H NMR (500 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.71 (dd, J=8.7, 1.0 Hz, 1H), 8.32-8.19 (m, 2H), 8.13 (dd, J=8.1, 1.1 Hz, 1H), 7.85 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.73 (ddd, J=8.2, 6.9, 1.1 Hz, 1H), 7.64 (dd, J=8.3, 7.3 Hz, 1H), 7.02 (t, J=7.6 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.85-6.77 (m, 1H), 2.62-2.52 (m, 4H), 2.15-2.05 (m, 1H), 1.96-1.87 (m, 1H), 1.85-1.72 (m, 1H), 1.70-1.42 (m, 3H), 1.36 (q, J=9.3 Hz, 1H), 1.28-1.04 (m, 2H), 1.03-0.90 (m, 1H). MS (APCI+) m/z 420.1 (M+H)⁺.

Example I-83 7-cyclobutyl-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was added 7-chloro-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (37 mg, 0.176 mmol) and PEPPSI IPentCl ([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II)) (15.11 mg, 0.018 mmol) in tetrahydrofuran (0.5 mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 1.4 mL, 0.70 mmol) was added. The reaction was heated at 50° C. for 16 hours. The reaction was purified using preparative reverse phase HPLC/MS method TFA1 to provide 7-cyclobutyl-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid. Into a 4 mL vial was added 7-cyclobutyl-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (10 mg, 0.043 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (16.65 mg, 0.087 mmol), and N,N-dimethylpyridin-4-amine (5.84 mg, 0.048 mmol) in dichloromethane (0.5 mL). Naphthalene-1-sulfonamide (9.90 mg, 0.048 mmol) was added. The reaction was stirred for 16 hours at room temperature. The solvent was removed under a stream of N₂ and the residue was redissolved in methanol. The reaction was purified using preparative reverse phase HPLC/MS method TFA8 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.70 (d, J=9.5 Hz, 1H), 8.27 (dd, J=7.4, 1.3 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H), 8.09-7.94 (m, 1H), 7.68-7.50 (m, 3H), 7.26-7.08 (m, 2H), 6.98 (dd, J=7.1, 1.3 Hz, 1H), 3.16-3.05 (m, 1H), 2.81 (dd, J=9.0, 5.7 Hz, 2H), 2.28-1.40 (m, 8H), 1.22 (s, 3H). MS (APCI+) m/z 420.1 (M+H)⁺.

Example I-84 (1R)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-84A (S)-7-bromo-4-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid

To a solution of (S)-4-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (450 mg, 2.341 mmol) in methanol (5 mL) and water (1.5 mL) at room temperature was added dibromine (0.180 mL, 3.51 mmol) dropwise. The mixture was stirred for 1 hour. The solvent was removed and water (2 mL) was added. The mixture was extracted with dichloromethane, and the combined organic layers were concentrated in vacuo. The mixture was purified by chromatography using a 24 g silica gel cartridge with a gradient of 0-100% ethyl acetate/heptanes over a period of 10 minutes to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.39 (s, 1H), 7.33 (d, J=8.6 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 3.91 (dd, J=9.6, 3.3 Hz, 1H), 3.78 (s, 3H), 2.95-2.87 (m, 2H), 2.41 (dq, J=13.2, 9.1 Hz, 1H), 2.17 (dddd, J=13.2, 7.5, 4.5, 3.3 Hz, 1H). MS (APCI+) m/z 271 (M+H)⁺.

Example I-84B 7-bromo-4-methoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-84A (0.41 g, 1.512 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (0.580 g, 3.02 mmol) and N,N-dimethylpyridin-4-amine (0.203 g, 1.664 mmol) were dissolved in N,N-dimethylacetamide (6.7 mL). The reaction was stirred at room temperature for 20 minutes and naphthalene-1-sulfonamide (0.313 g, 1.512 mmol) was added. After 16 hours, the N,N-dimethylacetamide was evaporated in vacuo. The residue was quenched with 1 N aqueous HCl (2.4 mL) to pH-2, and extracted with 50 mL dichloromethane. The solvent was evaporated in vacuo. The residue was purified by chromatography, eluting on a 24 g silica gel cartridge with a gradient of 0-100% ethyl acetate/heptanes over a period of 20 minute to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.72 (s, 1H), 8.67 (dd, J=8.7, 1.0 Hz, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.26 (dd, J=7.5, 1.3 Hz, 1H), 8.14-8.09 (m, 1H), 7.76 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.71-7.62 (m, 2H), 7.09 (d, J=8.7 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 3.97 (dd, J=9.7, 4.1 Hz, 1H), 3.70 (s, 3H), 2.77 (ddd, J=16.5, 9.2, 4.3 Hz, 1H), 2.72-2.62 (m, 1H), 2.37-2.27 (m, 1H), 1.82 (ddt, J=13.1, 8.7, 4.3 Hz, 1H). MS (APCI+) m/z 460 (M+H⁺).

Example I-84C (1R)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-84B (42 mg) was separated by chiral preparative SFC chromatography using a Whelk-O (S,S), column size 21×250 mm, 5 micron, serial Number: 43170, using a concentration of 4.2 mg/mL in methanol/dichlromethane 1:1 at a flow rate of 64 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.70 (s, 1H), 8.66 (dd, J=8.6, 1.0 Hz, 1H), 8.28-8.19 (m, 2H), 8.12-8.04 (m, 1H), 7.73 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.68-7.56 (m, 2H), 7.08 (d, J=8.6 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 3.94 (dd, J=9.7, 4.0 Hz, 1H), 3.68 (s, 3H), 2.77-2.58 (m, 2H), 2.29 (dtd, J=13.3, 9.4, 7.6 Hz, 1H), 1.81 (ddt, J=13.1, 8.6, 4.2 Hz, 1H). MS (APCI+) m/z 460 (M+H⁺), Br doublet. R_(T) (chiral SFC)=12.6 minutes.

Example I-85 (1S)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-84B (42 mg) was separated by chiral preparative SFC chromatography using a Whelk-O (S,S), column size 21×250 mm, 5 micron, serial Number: 43170, using a concentration of 4.2 mg/mL in methanol/dichlromethane 1:1 at a flow rate of 64 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.70 (s, 1H), 8.66 (dd, J=8.5, 1.0 Hz, 1H), 8.28-8.14 (m, 2H), 8.13-8.04 (m, 1H), 7.73 (ddd, J=8.4, 6.8, 1.4 Hz, 1H), 7.65 (q, J=7.5 Hz, 2H), 7.07 (d, J=8.6 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 3.94 (dd, J=9.9, 4.0 Hz, 1H), 3.68 (s, 3H), 2.75 (ddd, J=16.4, 9.2, 4.3 Hz, 1H), 2.66 (dt, J=16.3, 8.1 Hz, 1H), 2.33-2.23 (m, 1H), 1.81 (ddt, J=13.0, 8.5, 4.2 Hz, 1H). MS (APCI+) m/z 460 (M+H⁺), Br doublet. R_(T) (chiral SFC)=14.3 minutes.

Example I-86 (1R)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-86A 7-chloro-4-methoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A suspension of Example I-84B (100 mg, 0.217 mmol), copper(I) chloride (373 mg, 3.76 mmol) in N,N-dimethylacetamide (DMA) (0.9 mL) was purged with nitrogen and heated at 150° C. for 5 hours. The reaction was cooled, filtered, and washed with ethyl acetate. The filtrate was acidified with 1.5 mL 1 N aqueous HCl. Water (3 mL) was added and the mixture was extracted with ethyl acetate. The solvent was evaporated in vacuo and the residue was chromatographed using a 12 g silica gel cartridge with 0-100% ethyl acetate/heptanes over a period of 10 minutes to afford the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.73 (s, 1H), 8.66 (dd, J=8.6, 1.0 Hz, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.26 (dd, J=7.4, 1.3 Hz, 1H), 8.12 (dt, J=8.1, 0.9 Hz, 1H), 7.76 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.71-7.64 (m, 2H), 6.96 (d, J=8.7 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 4.03 (dd, J=9.5, 4.8 Hz, 1H), 3.70 (s, 3H), 2.78-2.62 (m, 2H), 2.31 (dtd, J=13.2, 9.3, 6.9 Hz, 1H), 1.81 (ddt, J=13.5, 8.7, 5.1 Hz, 1H). MS (APCI+) m/z 416 (M+H⁺).

Example I-86B (1R)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-86A (39 mg) was separated by chiral preparative SFC chromatography using a ChiralPak AD-H column size 21×250 mm, 5 micron, serial Number: ADHSAMA003-810291, using a concentration of 3.9 mg in methanol at a flow rate of 48 g/minutes CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.73 (s, 1H), 8.66 (dd, J=8.6, 1.1 Hz, 1H), 8.29-8.20 (m, 2H), 8.11 (dd, J=8.3, 1.4 Hz, 1H), 7.75 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.71-7.61 (m, 2H), 6.96 (d, J=8.7 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 4.01 (dd, J=9.5, 4.7 Hz, 1H), 3.70 (s, 3H), 2.79-2.62 (m, 2H), 2.30 (dtd, J=13.2, 9.2, 7.0 Hz, 1H), 1.82 (ddt, J=13.4, 8.6, 5.1 Hz, 1H). MS (APCI+) m/z 416 (M+H)⁺. R_(T) (chiral SFC)=2.85 minutes.

Example I-87 (1S)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-86A (39 mg) was separated by chiral preparative SFC chromatography using a ChiralPak AD-H column size 21×250 mm, 5 micron, serial Number: ADHSAMA003-810291, using a concentration of 3.9 mg in methanol at a flow rate of 48 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.73 (s, 1H), 8.66 (dd, J=8.7, 1.1 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.25 (dd, J=7.4, 1.2 Hz, 1H), 8.13-8.07 (m, 1H), 7.75 (ddd, J=8.5, 6.8, 1.4 Hz, 1H), 7.70-7.62 (m, 2H), 6.96 (d, J=8.7 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 4.02 (dd, J=9.5, 4.7 Hz, 1H), 3.70 (s, 3H), 2.78-2.63 (m, 2H), 2.31 (dtd, J=13.2, 9.2, 6.9 Hz, 1H), 1.82 (ddt, J=13.4, 8.6, 5.0 Hz, 1H). MS (APCI+) m/z 416 (M+H⁺). R_(T) (chiral SFC)=3.3 minutes.

Example I-88 5-cyclopropyl-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

Into a 4 mL vial was added Example I-41 (20 mg, 0.042 mmol) and PEPPSI IPentCl ([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II)) (3.63 mg, 4.22 μmol) in tetrahydrofuran (0.5 mL). Cyclopropylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.253 mL, 0.126 mmol) was added. The reaction was stirred at room temperature for 2 hours, at which point there was minimal conversion. Cyclopropylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.253 mL, 0.126 mmol) was added and the reaction was stirred for 16 hours at room temperature. The sample was directly purified using preparative HPLC/MS method TFA8 to afford the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.70 (d, J=8.6 Hz, 1H), 8.31-8.21 (m, 2H), 8.13 (d, J=8.2 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.76-7.69 (m, 1H), 7.67 (t, J=7.8 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.44 (d, J=8.5 Hz, 1H), 3.68 (t, J=5.7 Hz, 1H), 2.91 (s, 3H), 2.73-2.63 (m, 1H), 2.63-2.56 (m, 1H), 1.81-1.74 (m, 1H), 1.73-1.62 (m, 2H), 1.53-1.46 (m, 1H), 1.40-1.36 (m, 1H), 0.84-0.72 (m, 2H), 0.46-0.34 (m, 2H). MS (APCI+) m/z 436.1 (M+H)⁺.

Example I-89 (1S)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-89A 4,7-dimethoxy-2,3-dihydro-1H-indene-1-carbonitrile

In a 100 mL round bottom flask 4,7-dimethoxy-2,3-dihydro-1H-inden-1-one (1 g, 5.20 mmol) (CAS#52428-09-8, Aldrich) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TOSMIC, 1.016 g, 5.20 mmol) were dissolved in dimethoxyethane (15 mL) and methanol (0.358 mL, 8.84 mmol). The reaction was cooled to 0° C. in an ice bath under nitrogen. Solid potassium tert-butoxide (1.168 g, 10.41 mmol) was added in portions over 0.5 hour. The reaction was allowed to warm to room temperature over 1.5 hours, and heated at 42° C. for 1.5 hours. The solvent was removed in vacuo and the crude material was quenched with water (30 mL). The aqueous layer was extracted with ether (4×50 mL) and the organic suspension was filtered through diatomaceous earth. The filtered material was washed with ether. The solvent was removed in vacuo and the crude material was chromatographed using a 24 g silica gel cartridge with a gradient 0-100% ethyl acetate/heptanes over a period of 20 minutes to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 6.87 (dd, J=8.8, 0.6 Hz, 1H), 6.85-6.81 (m, 1H), 4.32 (ddd, J=9.1, 4.7, 0.7 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 2.99-2.89 (m, 1H), 2.88-2.79 (m, 1H), 2.49-2.42 (m, 1H), 2.28 (ddt, J=13.4, 8.6, 4.9 Hz, 1H).

Example I-89B 4,7-dimethoxy-2,3-dihydro-1H-indene-1-carboxylic acid

Example I-89A (0.33 g, 1.624 mmol) was dissolved in ethanol (5.41 mL). A solution of sodium hydroxide (0.649 g, 16.24 mmol) in 5.4 mL of water was added, and the resulting mixture was heated at 80° C. After 16 hours, the reaction was cooled in an ice bath and acidified with 6 M aqueous HCl (3.5 mL) to pH-2. The resulting precipitate was filtered and washed with water to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.08 (s, 1H), 6.75 (d, J=8.7 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 3.85 (dd, J=9.2, 4.6 Hz, 1H), 3.72 (s, 3H), 3.68 (s, 3H), 2.86 (ddd, J=15.8, 8.6, 7.0 Hz, 1H), 2.77 (ddd, J=16.0, 8.9, 4.9 Hz, 1H), 2.34 (dtd, J=12.9, 9.1, 7.0 Hz, 1H), 2.11 (ddt, J=13.3, 8.7, 4.8 Hz, 1H). MS (ESI+) m/z 223 (M+H⁺).

Example I-89C 4,7-dimethoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (43.2 mg, 0.354 mmol), and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (123 mg, 0.643 mmol) were combined in N,N-dimethylacetamide (1.2 mL). To the suspension was added Example I-89B (71.5 mg, 0.322 mmol). After 30 minutes, naphthalene-1-sulfonamide (60 mg, 0.290 mmol) was added. The reaction was stirred at room temperature for 18 hours. The N,N-dimethylacetamide was evaporated in vacuo. The residue was quenched with 1 mL water and 1 N aqueous citric acid (24 drops) to pH ˜4, extracted with dichloromethane and chromatographed using a 12 g silica gel cartridge, eluting with 0-100% ethyl acetate/heptanes over a period of 20 minutes to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.45 (s, 1H), 8.63 (dd, J=8.7, 1.1 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.21 (dd, J=7.4, 1.2 Hz, 1H), 8.12-8.07 (m, 1H), 7.75 (ddd, J=8.5, 6.8, 1.4 Hz, 1H), 7.69-7.60 (m, 2H), 6.62 (d, J=8.7 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 3.90 (dd, J=9.0, 5.6 Hz, 1H), 3.61 (s, 3H), 3.04 (s, 3H), 2.62 (t, J=7.4 Hz, 2H), 2.24-2.12 (m, 1H), 1.82-1.70 (m, 1H). MS (APCI+) m/z 412 (M+H⁺).

Example I-89D (1S)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-89C (33 mg) was separated by chiral preparative SFC chromatography using a ChiralPak AD-H column size 21×250 mm, 5 micron, serial Number: ADHSAMA003-810291, using a concentration of 8.2 mg in methanol at a flow rate of 48 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.45 (s, 1H), 8.63 (dd, J=8.7, 1.1 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.21 (dd, J=7.4, 1.2 Hz, 1H), 8.12-8.07 (m, 1H), 7.75 (ddd, J=8.5, 6.8, 1.4 Hz, 1H), 7.69-7.60 (m, 2H), 6.62 (d, J=8.7 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 3.90 (dd, J=9.0, 5.6 Hz, 1H), 3.61 (s, 3H), 3.04 (s, 3H), 2.62 (t, J=7.4 Hz, 2H), 2.24-2.12 (m, 1H), 1.82-1.70 (m, 1H). MS (APCI+) m/z 412 (M+H⁺). R_(T) (chiral SFC)=3.0 minutes.

Example I-90 (1R)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-89C (33 mg) was separated by chiral preparative SFC chromatography using a ChiralPak AD-H column size 21×250 mm, 5 micron, serial Number: ADHSAMA003-810291, using a concentration of 8.2 mg in methanol at a flow rate of 48 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.45 (s, 1H), 8.63 (dd, J=8.7, 1.1 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.21 (dd, J=7.4, 1.2 Hz, 1H), 8.12-8.07 (m, 1H), 7.75 (ddd, J=8.5, 6.8, 1.4 Hz, 1H), 7.69-7.60 (m, 2H), 6.62 (d, J=8.7 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 3.90 (dd, J=9.0, 5.6 Hz, 1H), 3.61 (s, 3H), 3.04 (s, 3H), 2.62 (t, J=7.4 Hz, 2H), 2.24-2.12 (m, 1H), 1.82-1.70 (m, 1H). MS (APCI+) m/z 412 (M+H⁺). R_(T) (chiral SFC)=4.1 minutes.

Example I-91 (1S)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-91A 4,7-dimethoxy-N-(quinolin-5-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (43.0 mg, 0.352 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (123 mg, 0.640 mmol) were combined in N,N-dimethylacetamide (1.2 mL). To this suspension was added Example I-89B (71.1 mg, 0.320 mmol). After 30 minutes, quinoline-5-sulfonamide (60 mg, 0.288 mmol) was added. The reaction was stirred at room temperature for 16 hours. The N,N-dimethylacetamide was evaporated in vacuo, and the residue was quenched with 1 N aqueous citric acid (24 drops) to pH ˜4. The precipitate was filtered and chromatographed using a 4 g silica gel cartridge with 0-100% ethyl acetate/heptanes over a period of 5 minutes to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.56 (s, 1H), 9.07-8.97 (m, 2H), 8.34-8.25 (m, 2H), 7.89 (dd, J=8.4, 7.4 Hz, 1H), 7.77 (dd, J=8.8, 4.2 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 6.48 (d, J=8.7 Hz, 1H), 3.88 (dd, J=9.1, 5.6 Hz, 1H), 3.62 (s, 3H), 3.03 (s, 3H), 2.64 (ddd, J=8.5, 6.6, 4.2 Hz, 2H), 2.20 (dtd, J=13.0, 8.6, 6.5 Hz, 1H), 1.78 (ddt, J=12.4, 8.4, 6.1 Hz, 1H). MS (APCI+) m/z 413 (M+H⁺).

Example I-91B (1S)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-91A (60 mg) was separated by chiral preparative SFC chromatography using a ChiralPak AD-H column size 21×250 mm, 5 micron, serial Number: ADHSAMA003-810291, using a concentration of 6.0 mg in methanol at a flow rate of 56 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.56 (s, 1H), 9.07-8.97 (m, 2H), 8.34-8.25 (m, 2H), 7.89 (dd, J=8.4, 7.4 Hz, 1H), 7.77 (dd, J=8.8, 4.2 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 6.48 (d, J=8.7 Hz, 1H), 3.88 (dd, J=9.1, 5.6 Hz, 1H), 3.62 (s, 3H), 3.03 (s, 3H), 2.64 (ddd, J=8.5, 6.6, 4.2 Hz, 2H), 2.20 (dtd, J=13.0, 8.6, 6.5 Hz, 1H), 1.78 (ddt, J=12.4, 8.4, 6.1 Hz, 1H). MS (APCI+) m/z 413 (M+H⁺). R_(T) (chiral SFC)=2.75 minute.

Example I-92 (1R)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-91A (60 mg) was separated by chiral preparative SFC chromatography using a ChiralPak AD-H column size 21×250 mm, 5 micron, serial Number: ADHSAMA003-810291, using a concentration of 6.0 mg in methanol at a flow rate of 56 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.56 (s, 1H), 9.07-8.97 (m, 2H), 8.34-8.25 (m, 2H), 7.89 (dd, J=8.4, 7.4 Hz, 1H), 7.77 (dd, J=8.8, 4.2 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 6.48 (d, J=8.7 Hz, 1H), 3.88 (dd, J=9.1, 5.6 Hz, 1H), 3.62 (s, 3H), 3.03 (s, 3H), 2.64 (ddd, J=8.5, 6.6, 4.2 Hz, 2H), 2.20 (dtd, J=13.0, 8.6, 6.5 Hz, 1H), 1.78 (ddt, J=12.4, 8.4, 6.1 Hz, 1H). MS (APCI+) m/z 413 (M+H)⁺. R_(T) (chiral SFC)=3.3 minute.

Example I-93 (1S)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-93A 7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one

A mixture of 7-methoxy-2,3-dihydro-1H-inden-1-one [CAS#34985-41-6](1 g, 6.17 mmol), trimethyl(trifluoromethyl)silane (1.753 g, 12.33 mmol), silver(I) fluoride (0.196 g, 1.541 mmol) and PhI(OAc)₂ ((diacetoxyiodo)benzene 3.97 g, 12.33 mmol) in dimethyl sulfoxide (10 mL) was stirred at 45° C. for 16 hours. Water (10 mL) was added. The mixture was extracted with ethyl acetate (3×20 mL), and the combined extracts were washed with brine. The organic layer was dried over MgSO₄, filtered, and concentrated. The residue was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.79 (dd, J=8.6, 0.8 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 4.01 (s, 3H), 3.28-3.22 (m, 2H), 2.76-2.68 (m, 2H). MS (ESI+) m/z 231.0 (M+H)⁺.

Example I-93B 7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carbonitrile

The mixture of Example I-93A (0.290 g, 1.260 mmol) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TOSMIC, 0.320 g, 1.638 mmol) were dissolved in dimethoxyethane (12.60 mL). The reaction mixture was cooled to −8° C. (internal temperature) with ice/acetone/dry ice under nitrogen. Solid potassium tert-butoxide (0.325 g, 2.90 mmol) was added in portions keeping the internal temperature <−5° C. over about 30 minutes, and allowed to warm to room temperature and stir for 16 hours. The solvent was removed in vacuo and the crude residue was quenched with water (20 mL). The aqueous layer was extracted with ether (3×60 mL). The solvent was removed and the crude residue was chromatographed using a 25 g silica gel cartridge, eluting with an ethyl acetate in hexane at 0-50% gradient to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.57 (d, J=8.5 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.14 (dd, J=8.4, 5.3 Hz, 1H), 3.96 (s, 3H), 3.32 (dt, J=16.5, 8.1 Hz, 1H), 3.17 (dtd, J=14.4, 6.5, 3.2 Hz, 1H), 2.66-2.46 (m, 2H). MS (APCI+) m/z 258 (M+H⁺).

Example I-93C 7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxylic acid

A mixture of Example I-93B (170 mg, 0.705 mmol) and sodium hydroxide (282 mg, 7.05 mmol) in ethanol (6 mL) was stirred at 90° C. for 16 hours. The solvent was removed under reduced pressure and water (3 mL) was added. The mixture was adjusted to pH 1˜2 by adding 2N aqueous HCl and extracted with dichloromethane (3×20 mL). The combined extracts was washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was purified via chromatography on a 12 g cartridge, eluting with ethyl acetate/methanol (9:1) in heptanes at 0-70% gradient to provide title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.28 (s, 1H), 7.56 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 3.92 (dd, J=9.4, 4.6 Hz, 1H), 3.83 (s, 3H), 3.14-2.96 (m, 2H), 2.46-2.35 (m, 1H), 2.19 (ddt, J=13.2, 8.6, 4.8 Hz, 1H). MS[APCI(+)] m/z 258 (M+H)⁺.

Example I-93D 7-methoxy-N-(naphthalen-1-ylsulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide

A mixture of Example I-93C (47 mg, 0.181 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (69.3 mg, 0.361 mmol) and N,N-dimethylpyridin-4-amine (24.27 mg, 0.199 mmol) in dichloromethane (2 mL) was stirred at room temperature for 30 minutes. Naphthalene-1-sulfonamide (41.2 mg, 0.199 mmol) was added. The mixture was stirred for another 2 hours. The reaction mixture without work up was loaded on a 12 g silica gel cartridge and chromatographed eluting with methanol in ethyl acetate (0-15% gradient) to provide the title compound. MS [APCI(+)], m/z 450.3 (M+H⁺).

Example I-93E (1S)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-93D (62 mg, 0.138 mmol) was separated via chiral SFC using Column: ChiralPak AD-H, Column Size: 21×250 mm, 5 micron, Concentration: 6 mg/mL in methanol, and Co-Solvent: methanol. The title compound was the first fraction at 3.05 minutes. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.64 (s, 1H), 8.67 (dd, J=8.6, 1.1 Hz, 1H), 8.34-8.21 (m, 2H), 8.14 (dd, J=8.3, 1.3 Hz, 1H), 7.80 (ddd, J=8.6, 6.9, 1.4 Hz, 1H), 7.75-7.63 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 3.98 (dd, J=9.2, 5.5 Hz, 1H), 3.17 (s, 3H), 2.90 (t, J=7.6 Hz, 2H), 2.40-2.26 (m, 1H), 1.86 (dtd, J=12.9, 7.3, 5.5 Hz, 1H). MS(ESI+) m/z 449.9 (M+H⁺).

Example I-94 (1R)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide

The title compound was the second fraction at 4.87 minutes during the chiral SFC separation described in Example I-93E. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.65 (s, 1H), 8.67 (dd, J=8.6, 1.0 Hz, 1H), 8.37-8.23 (m, 2H), 8.14 (dd, J=8.2, 1.3 Hz, 1H), 7.79 (ddd, J=8.6, 6.9, 1.4 Hz, 1H), 7.76-7.61 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 3.97 (dd, J=9.2, 5.5 Hz, 1H), 3.18 (s, 3H), 2.90 (t, J=7.6 Hz, 2H), 2.38-2.24 (m, 1H), 1.86 (dtd, J=12.9, 7.3, 5.4 Hz, 1H). MS(ESI+) m/z 450 (M+H)⁺.

Example I-95 (1S)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-95A 7-methoxy-N-(quinolin-5-ylsulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide

A mixture of Example I-93C (45 mg, 0.173 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (66.3 mg, 0.346 mmol) and N,N-dimethylpyridin-4-amine (23.24 mg, 0.190 mmol) in dichloromethane (2 mL) was stirred at room temperature for 30 minutes. Quinoline-5-sulfonamide (39.6 mg, 0.190 mmol) was added. The mixture was stirred for 2 hours. The reaction mixture was purified via chromatography, eluting with methanol in ethyl acetate at 0-15% to provide the title compound. MS [APCI(+)], m/z 451.27 (M+H)⁺.

Example I-95B (1S)-7-methoxy-N-(5-quinolylsulfonyl)-4-(trifluoromethyl)indane-1-carboxamide

Racemic Example I-95A (60 mg, 0.133 mmol) was separated via chiral SFC using Column: ChiralPak AD-H, Column Size: 21×250 mm, 5 micron, Concentration: 6 mg/mL in methanol, Co-Solvent: methanol. The first fraction at 3.05 minute was the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.75 (s, 1H), 9.10 (dd, J=4.2, 1.6 Hz, 1H), 9.05 (dt, J=8.7, 1.3 Hz, 1H), 8.38 (dt, J=8.4, 1.1 Hz, 1H), 8.34 (dd, J=7.4, 1.3 Hz, 1H), 7.95 (dd, J=8.5, 7.4 Hz, 1H), 7.84 (dd, J=8.8, 4.2 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 3.98 (dd, J=9.2, 5.7 Hz, 1H), 3.17 (s, 3H), 2.92 (t, J=7.4 Hz, 2H), 2.36 (ddt, J=13.1, 9.3, 7.4 Hz, 1H), 1.88 (dtd, J=13.2, 7.4, 5.7 Hz, 1H). MS(ESI+) m/z 451.2 (M+H)⁺.

Example I-96 (1R)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide

The title compound was the second fraction at 4.87 minutes from the chiral SFC separation described in Example I-95B. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.75 (s, 1H), 9.10 (dd, J=4.2, 1.6 Hz, 1H), 9.05 (dt, J=8.8, 1.3 Hz, 1H), 8.41-8.31 (m, 2H), 7.95 (dd, J=8.4, 7.5 Hz, 1H), 7.83 (dd, J=8.8, 4.2 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 3.97 (dd, J=9.2, 5.7 Hz, 1H), 3.18 (s, 3H), 2.92 (t, J=7.5 Hz, 2H), 2.35 (ddt, J=13.1, 9.5, 7.5 Hz, 1H), 1.88 (dtd, J=13.2, 7.5, 5.6 Hz, 1H). MS(ESI+) m/z 451.2 (M+H)⁺.

Example I-97 4-chloro-1-ethyl-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-97A 1-methyl-1H-indazole-7-sulfonamide

n-Butyllithium (2.5 M in tetrahydrofuran, 0.758 mL, 1.895 mmol) and n-Bu₂Mg (di-n-butyl magnesium, 1.0 M in heptane, 5.69 mL, 5.69 mmol) were charged into a nitrogen filled three-necked flask at room temperature. A solution of 7-bromo-1-methyl-1H-indazole (1.000 g, 4.74 mmol) in tetrahydrofuran (15 mL) was added dropwise to the n-Bu₃MgLi solution at −25° C. and the mixture was stirred at −10° C. for 1 hour. The LC/MS indicated the consumption of the reaction substrates. The resulting mixture was added to a solution of SO₂Cl₂ (0.959 mL, 11.85 mmol) in toluene (10 mL) at −10° C. and the mixture was stirred for 20 minutes at −10° C. The LC/MS indicated the completion of the reaction, and that most of sulfonyl chloride product was formed. The organic solvents were removed by rotary evaporation to give the crude material. The crude material was used in the next step without purification. Ammonium hydroxide (15 mL) was added to the crude material at room temperature, and the mixture was stirred for 15 minutes. After completion, the mixture was concentrated by rotary evaporation. The crude product was diluted with ethyl acetate (200 mL), washed with saturated NaCl solution (50 mL), dried over Na₂SO₄, filtered, and concentrated. The crude material was purified by Combi-Flash chromatography (H₂O (0.01% TFA) (A)/Methanol (B), Gradient from 20-50% of B at 10 minute-20 minute, and concentrated to provide the title compound. ¹H NMR: (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.27 (s, 1H), 8.05 (dd, J=8.0, 0.9 Hz, 1H), 7.93 (dd, J=8.0, 0.9 Hz, 1H), 7.92 (s, 2H), 7.28 (t, J=7.7 Hz, 1H), 4.37 (s, 3H). LCMS (ESI+) m/z 212.1 (M+H)⁺.

Example I-97B 4-chloro-1-ethyl-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-17A (26.6 mg, 0.12 mmol, 1.0 equivalent), EDCI HCl (1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 44.9 mg, 0.24 mmol, 2.0 equivalents) and DMAP (4-dimethylaminopyridine) (15.9 mg, 0.13 mmol, 1.1 equivalents) was dissolved in dichloromethane (0.5 mL). 1-Methyl-1H-indazole-7-sulfonamide (25 mg, 0.12 mmol, 1.0 equivalent) in dichloromethane (0.25 mL) was added and the reaction was stirred at room temperature for 16 hours. The solvent was removed under a stream of N₂. The residue was dissolved in methanol and purified using preparative reverse phase HPLC/MS method TFA6 to afford the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.28 (s, 1H), 8.14 (dd, J=8.0, 1.1 Hz, 1H), 8.06 (dd, J=7.5, 1.1 Hz, 1H), 7.35-7.24 (m, 2H), 7.22-7.11 (m, 2H), 4.25 (s, 3H), 2.85 (t, J=7.3 Hz, 2H), 2.47 (dt, J=13.0, 7.4 Hz, 1H), 2.09-1.98 (m, 2H), 1.76-1.65 (m, 1H), 0.62 (t, J=7.4 Hz, 3H). MS (APCI+) m/z 418.1 (M+H)⁺.

Example I-98 4-bromo-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-19B (32.1 mg, 0.12 mmol, 1.0 equivalent), EDCI HCl (N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride) (44.9 mg, 0.24 mmol, 2.0 equivalents) and DMAP (4-dimethylaminopyridine) (15.9 mg, 0.13 mmol, 1.1 equivalents) were dissolved in dichloromethane (0.5 mL). 1-Methyl-1H-indazole-7-sulfonamide (25 mg, 0.12 mmol, 1.0 equivalent) in dichloromethane (0.25 mL) was added and the reaction was stirred at room temperature for 16 hours. The solvent was removed under a stream of N₂. The residue was dissolved in methanol and purified using preparative reverse phase HPLC/MS method TFA6 to afford the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.35 (s, 1H), 8.20 (dd, J=8.0, 1.1 Hz, 1H), 8.09 (dd, J=7.6, 1.1 Hz, 1H), 7.37-7.30 (m, 2H), 6.65 (d, J=8.8 Hz, 1H), 4.43 (s, 3H), 4.13 (dd, J=9.1, 5.9 Hz, 1H), 3.23 (s, 3H), 2.92-2.78 (m, 2H), 2.47-2.36 (m, 1H), 2.08-1.95 (m, 1H). MS (APCI+) m/z 463.9 (M+H)⁺.

Example I-99 4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was added Example I-98 (14.5 mg, 0.031 mmol) and PEPPSI IPentCl ([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II)) (2.69 mg, 3.12 μmol) in tetrahydrofuran (1 mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.2 mL, 0.100 mmol) was added. The reaction was stirred for 16 hours at room temperature. The sample was directly purified using preparative HPLC/MS method TFA7 to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.31 (s, 1H), 8.15 (d, J=7.9 Hz, 1H), 8.06 (d, J=7.3 Hz, 1H), 7.31 (t, J=7.7 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 4.43 (s, 3H), 3.96 (t, J=7.5 Hz, 1H), 3.47-3.35 (m, 1H), 3.22 (s, 3H), 2.87-2.63 (m, 2H), 2.41-2.27 (m, 1H), 2.27-2.08 (m, 2H), 2.07-1.85 (m, 4H), 1.81-1.66 (m, 1H). MS (APCI+) m/z 440.1 (M+H)⁺.

Example I-100 4-bromo-7-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-100A 3-methylimidazo[1,2-a]pyridine-5-sulfonamide hydrobromic acid

6-Aminopyridine-2-sulfonamide (53 mg, 0.306 mmol) (CAS#75903-58-1) and 2-bromo-1,1-diethoxypropane (0.101 mL, 0.573 mmol) were combined in ethanol (0.5 mL). The mixture was heated to reflux. The reaction was heated at reflux for 16 hours and the solvent had evaporated. The residue was triturated with ethyl ether and the resulting precipitate was dried under a stream of nitrogen to provide the title compound as a hydrobromic acid salt. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.73 (s, 2H), 8.10 (td, J=4.5, 1.3 Hz, 2H), 8.01 (dd, J=7.4, 1.3 Hz, 1H), 7.93 (dd, J=8.9, 7.4 Hz, 1H), 2.81 (d, J=1.0 Hz, 3H). MS (ESI+) m/z 212 (M+H⁺).

Example I-100B 4-bromo-7-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (48.8 mg, 0.399 mmol), and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (72.9 mg, 0.380 mmol) were combined in N,N-dimethylacetamide (0.9 mL). To the suspension was added Example I-19B (51.6 mg, 0.190 mmol). After 30 minutes, Example I-100A (50 mg, 0.171 mmol) was added. The reaction was stirred at room temperature for 18 hours. The N,N-dimethylacetamide was evaporated in vacuo. The residue was quenched with 1 N aqueous citric acid (23 drops) to pH ˜4, and extracted with 2.5 mL 25% isopropyl alcohol/dichloromethane. The solvent was evaporated in vacuo. The residue was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A). The material was triturated with 1 mL of ether and filtered. The material was triturated with 1 mL methanol and filtered to provide the title compound as a trifluoroacetic acid salt. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.00-7.92 (m, 2H), 7.90 (s, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 3.87 (bs, 1H), 3.44 (s, 3H), 2.94-2.72 (m, 2H), 2.85 (s, 3H), 2.30 (dtd, J=13.0, 9.0, 7.0 Hz, 1H), 2.03 (ddt, J=13.3, 9.0, 4.7 Hz, 1H). MS (APCI+) m/z 464 (M+H)⁺.

Example I-101 4-bromo-7-methoxy-N-(2-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-101A 2-methylimidazo[1,2-a]pyridine-5-sulfonamide, Hydrochloric Acid

6-Aminopyridine-2-sulfonamide (50 mg, 0.289 mmol) (CAS#75903-58-1) and 1-chloropropan-2-one (0.046 mL, 0.577 mmol) were combined in ethanol (0.5 mL) and heated to reflux. The reaction was heated for 16 hours and the solvent was evaporated. The material was triturated with diethyl ether and the resulting precipitate was dried under a stream of nitrogen to provide the title compound as a hydrochloric acid salt. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 8.64 (s, 2H), 8.32-8.27 (m, 1H), 8.11 (dt, J=8.7, 1.1 Hz, 1H), 7.94 (dd, J=8.7, 7.4 Hz, 1H), 7.90 (dd, J=7.4, 1.4 Hz, 1H), 2.54 (d, J=1.0 Hz, 3H).

Example I-101B 4-bromo-7-methoxy-N-(2-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (43.7 mg, 0.358 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (65.4 mg, 0.341 mmol) were combined in N,N-dimethylacetamide (0.8 mL). To the suspension was added Example I-19B (46.2 mg, 0.170 mmol). After 30 minutes, Example I-101A (38 mg, 0.153 mmol) was added. The reaction was stirred at room temperature for 18 hours. The N,N-dimethylacetamide was evaporated in vacuo. The residue was quenched with 1 N aqueous citric acid (25 drops) to pH ˜4, and extracted with 2.5 mL 25% isopropyl alcohol/dichloromethane. The solvent was evaporated in vacuo. The residue was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)t. The material was triturated with 1 mL of dichloromethane, and filtered. The filtrate was concentrated to dryness, triturated with 0.5 mL methanol, filtered, and combined with previous filtered material to provide the title compound as a trifluoroacetic acid salt. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.11 (s, 1H), 7.94-7.87 (m, 1H), 7.70 (d, J=4.9 Hz, 2H), 7.29 (d, J=8.6 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 3.87 (bs, 1H), 3.34 (s, 1H), 2.91-2.69 (m, 2H), 2.49 (s, 3H), 2.35-2.19 (m, 1H), 1.97 (ddt, J=13.6, 9.4, 5.1 Hz, 1H). MS (APCI+) m/z 465 (M+H)⁺.

Example I-102 2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide Example I-102A 5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol

A 2 L flask under an atmosphere of nitrogen was charged with tetrahydrofuran (250 mL, 3051 mmol), cooled to 0° C., treated dropwise with 2.5 M n-butyllithium in hexanes (77.6 mL, 194 mmol), and stirred at room temperature for 16 hours. In a separate flask, a solution of 2,2,6,6-tetramethylpiperidine (24.2 g, 171 mmol) in tetrahydrofuran (120 mL) at 0° C. under N₂ was treated dropwise with 2.5 M n-butyllithium in hexanes (69 mL, 173 mmol). The mixture was stirred at 0° C. for 30 minutes. The solution of tetrahydrofuran/n-butyllithium was cooled to −78° C. and was treated with a solution of 3-bromoanisole (30 g, 160 mmol) in tetrahydrofuran (120 mL). The mixture was treated dropwise over 30 minutes with the solution of lithium tetramethylpiperidine, stirred at −78° C. for 45 minutes, treated with a solution of ammonium chloride (68.6 g, 1283 mmol) in water (450 mL) and was allowed to stir at room temperature for 10 minutes. The mixture was concentrated to remove ˜400 mL of tetrahydrofuran. The mixture was extracted with ethyl acetate (3×200 mL). The combined ethyl acetate layers were washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was chromatographed on silica gel, eluting with a gradient of 10% to 50% ethyl acetate in heptanes to provide the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 7.22 (dd, J=7.3, 8.3 Hz, 2H), 6.74-6.70 (m, 2H), 5.35 (ddd, J=1.9, 4.5, 9.6 Hz, 1H), 3.97 (s, 3H), 3.60 (dd, J=4.5, 14.4 Hz, 1H), 3.02-2.98 (m, 1H), 2.36 (d, J=9.6 Hz, 1H). MS (APCI+) m/z 151 (M+H)⁺.

Example I-102B 5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one

A solution of oxalyl chloride (6.56 mL, 74.9 mmol) in dichloromethane (90 mL) was cooled to −78° C., treated dropwise with a solution of dimethyl sulfoxide (10.63 mL, 150 mmol) in dichloromethane (70 mL), stirred at −78° C. for 20 minutes, treated dropwise with a solution of Example I-102A (5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol) (7.5 g, 49.9 mmol) in dichloromethane (70 mL), stirred at −78° C. for 2 hours, treated dropwise with triethylamine (41.8 mL, 300 mmol), and allowed to stir at room temperature. When the mixture reached 0° C., water (100 mL) was added. The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted with dichloromethane (˜100 mL). The combined dichloromethane layers were washed with brine, dried (MgSO₄), filtered, and concentrated. The residue chromatographed on silica gel, eluting with a gradient of 5% to 20% ethyl acetate in heptanes to provide the title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.42 (dd, J=7.1, 8.4 Hz, 1H), 7.02 (dq, J=0.7, 7.1 Hz, 1H), 6.80 (dq, J=0.7, 8.5 Hz, 1H), 4.11 (s, 3H), 3.92 (t, J=0.8 Hz, 2H).

Example I-102C (E)-2-methoxy-8-(methoxymethylene)bicyclo[4.2.0]octa-1,3,5-triene and (Z)-2-methoxy-8-(methoxymethylene)bicyclo[4.2.0]octa-1,3,5-triene

A solution of (methoxymethyl)triphenylphosphonium chloride (9.72 g, 28.3 mmol) in tetrahydrofuran (90 mL) under N₂ at room temperature was treated with 1 M potassium tert-butoxide in tetrahydrofuran (26.3 mL, 26.3 mmol), and stirred at room temperature for 20 minutes. The mixture was treated with a solution of Example I-102B (5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one) (3 g, 20.25 mmol) in tetrahydrofuran (20 mL), stirred for 16 hours, concentrated without heat to remove majority of tetrahydrofuran and partitioned between methyl tert-butyl ether (100 mL) water (50 mL). The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (30 mL). The combined methyl tert-butyl ether layers were washed with brine, dried (MgSO₄), filtered, concentrated, dissolved in dichloromethane (5 mL), diluted with heptanes (˜45 mL), and allowed to stand at room temperature for 10 minutes. The material was removed by filtration. The filtrate was concentrated and the residue was chromatographed on silica gel, eluting with a gradient of 5% to 15% ethyl acetate in heptanes to provide the less polar isomer as the first to elute, (E)-2-methoxy-8-(methoxymethylene)bicyclo[4.2.0]octa-1,3,5-triene, followed by the more polar isomer as the second to elute, (Z)-2-methoxy-8-(methoxymethylene)bicyclo[4.2.0]octa-1,3,5-triene. NMR of less polar isomer: ¹H NMR (501 MHz, CDCl₃) δ ppm 7.07 (dd, J=7.2, 8.4 Hz, 1H), 6.76 (dd, J=0.5, 7.2 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 6.52 (t, J=1.4 Hz, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 3.65-3.64 (m, 2H). LC/MS (APCI+) m/z 218 (M+CH₃CN+H)⁺. ¹H NMR of more polar isomer: ¹H NMR (501 MHz, CDCl₃) δ ppm 7.14 (dd, J=7.1, 8.5 Hz, 1H), 6.77 (dd, J=0.8, 7.2 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.93 (t, J=0.9 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.45 (d, J=0.9 Hz, 2H). LC/MS (APCI+) m/z 218 (M+CH₃CN+H)⁺.

Example I-102D 5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbaldehyde

A solution of the less polar isomer from Example I-102C ((E)-2-methoxy-8-(methoxymethylene)bicyclo[4.2.0]octa-1,3,5-triene) (1.72 g, 9.76 mmol) in tetrahydrofuran (30 mL) was treated with 3 M aqueous HCl (25 mL) in portions over 2 minutes. The mixture was stirred at room temperature for 2 hours, heated to 55° C. for 1 hour, cooled, diluted with water (˜90 mL) and extracted with methyl tert-butyl ether (twice, ˜150 mL and ˜75 mL). The combined methyl tert-butyl ether layers were washed with brine, dried (MgSO₄), filtered, and concentrated to provide impure aldehyde. In a separate flask, a solution of more polar isomer from Example I-102C ((Z)-2-methoxy-8-(methoxymethylene)bicyclo[4.2.0]octa-1,3,5-triene) (0.97 g, 5.50 mmol) in tetrahydrofuran (˜20 mL) was treated with 3 M aqueous HCl in water (18.35 mL, 55.0 mmol) in portions over 2 minutes. The mixture was stirred at room temperature for 2 hours, diluted with water (˜60 mL) and extracted with methyl tert-butyl ether (twice, ˜80 mL and ˜40 mL). The combined methyl tert-butyl ether layers were washed with brine, dried (MgSO₄), filtered, and concentrated to provide pure aldehyde. The impure aldehyde and pure aldehyde were combined and chromatographed on silica gel, eluting with a gradient of 5 to 30% ethyl acetate to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.74 (d, J=4.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 6.77-6.73 (m, 2H), 4.31-4.28 (m, 1H), 3.80 (s, 3H), 3.41 (dd, J=5.3, 14.5 Hz, 1H), 3.33 (dd, J=2.4, 14.5 Hz, 1H).

Example I-102E 5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid

A solution of Example I-102D (5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbaldehyde) (1.83 g, 11.28 mmol) in acetone (55 mL) was cooled to 0° C. and treated dropwise with 2 M CrO₃ in aqueous H₂SO₄ (Aldrich catalog #758035-25ML) (11.28 mL, 22.57 mmol), stirred at 0° C. for 30 minutes, quenched with the dropwise addition of 2-propanol (4.35 mL, 56.4 mmol), and stirred at room temperature for 15 minutes. The mixture was diluted with acetone (50 mL) and the material was removed by filtration through diatomaceous earth and washed with acetone. The combined filtrates were concentrated in vacuo with gentle heating (˜30° C.) to remove the acetone. The residue was partitioned between methyl tert-butyl ether (˜100 mL) and water (˜40 mL). The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (˜50 mL). The combined methyl tert-butyl ether layers were washed with brine, dried (MgSO₄), filtered, and concentrated to provide the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 7.24-7.21 (m, 1H), 6.75-6.73 (m, 2H), 4.38 (dd, J=2.4, 5.6 Hz, 1H), 3.87 (s, 3H), 3.52-3.48 (m, 1H), 3.42-3.38 (m, 1H).

Example I-102F ethyl 5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate

A solution of Example I-102E (5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid) (1.78 g, 9.99 mmol) in ethanol (50 mL) was treated with concentrated H₂SO₄ (0.1 mL), heated to 80° C. for 1 hour, cooled, treated with NaHCO₃ (˜1 g), stirred for 5 minutes, and concentrated. The residue was partitioned between methyl tert-butyl ether (75 mL) and water (30 mL). The methyl tert-butyl ether layer was washed with brine, dried (MgSO₄), filtered, and concentrated to provide the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 7.20 (t, J=7.9 Hz, 1H), 6.73-6.71 (m, 2H), 4.35 (dd, J=2.6, 5.7 Hz, 1H), 4.21 (qd, J=1.7, 7.2 Hz, 2H), 3.85 (s, 3H), 3.45 (dd, J=5.7, 14.0 Hz, 1H), 3.34 (dd, J=2.6, 14.0 Hz, 1H), 1.28 (t, J=7.1 Hz, 3H). MS (ESI+) m/z 248 (M+MeCN+H)⁺.

Example I-102G ethyl 2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate and ethyl 4-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate

A solution of Example I-102F (ethyl 5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate) (1.9 g, 9.21 mmol) in CH₃CN (90 mL) was cooled to 0° C., treated with a solution of N-bromosuccinimide (1.640 g, 9.21 mmol) in CH₃CN (20 mL), stirred overnight at room temperature, and concentrated to dryness. The residue was taken up in dichloromethane (˜5 mL), diluted with heptanes, and was allowed to stand at room temperature for ˜15 minutes while a material precipitated. The material was removed by filtration and was discarded. The filtrate was concentrated to dryness. The residue was chromatographed on silica gel, eluting with a gradient of 5% to 15% methyl tert-butyl ether in heptanes to provide a mixture of ethyl 2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate and ethyl 4-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate in a 12:1 ratio. NMR/MS of the major component, ethyl 2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate: ¹H NMR (500 MHz, CDCl₃) δ ppm 7.25 (dd, J=0.8, 8.9 Hz, 1H), 6.64-6.62 (m, 1H), 4.28 (ddd, J=0.8, 2.6, 5.7 Hz, 1H), 4.24-4.19 (m, 2H), 3.83 (s, 3H), 3.38 (ddd, J=0.8, 5.7, 14.1 Hz, 1H), 3.28 (ddd, J=0.8, 2.6, 14.1 Hz, 1H), 1.28 (t, J=7.1 Hz, 3H). MS (ESI+) m/z 285,287 (M+H)⁺.

Example I-102H 2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid

A solution of Example I-102G (ethyl 2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate) (542 mg, 1.900 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (139 mg, 0.190 mmol) in tetrahydrofuran (5 mL) was treated with 0.5 M cyclobutylzinc bromide in tetrahydrofuran (11.4 mL, 5.70 mmol), stirred at room temperature for 2 hours, and partitioned between methyl tert-butyl ether (100 mL) and 1 M aqueous HCl (50 mL). The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (50 mL). The combined methyl tert-butyl ether layers were washed with brine, dried (MgSO₄), filtered, concentrated, and chromatographed on silica gel, eluting with 5% methyl tert-butyl ether in heptanes provided ethyl 2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate, with a minor impurity. ¹H NMR of major component, ethyl 2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate: ¹H NMR (400 MHz, CDCl₃) δ ppm 6.99 (d, J=8.6 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 4.32 (dd, J=2.6, 5.6 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 3.47 (dd, J=5.6, 13.8 Hz, 1H), 3.44-3.40 (m, 1H), 3.37 (dd, J=2.7, 13.8 Hz, 1H), 2.32-2.23 (m, 2H), 2.21-2.09 (m, 2H), 2.05-1.92 (m, 1H), 1.89-1.79 (m, 1H), 1.28 (t, J=7.1 Hz, 3H). A solution of ethyl 2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate (173 mg, 0.665 mmol) in tetrahydrofuran (1.5 mL) and methanol (1.5 mL) was treated with 1 M aqueous NaOH (1.5 mL), stirred at room temperature for 30 minutes, and partitioned between methyl tert-butyl ether (˜75 mL) and 1 M aqueous HCl (15 mL). The methyl tert-butyl ether layer was washed with brine, dried (MgSO₄), filtered, and concentrated to provide the corresponding carboxylic acid, 2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid, which contained an impurity. Crude 2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid was dissolved in methanol (˜5 mL), treated with 1 drop of concentrated H₂SO₄, heated to 60° C. for 2 hours, cooled, treated with NaHCO₃ (˜1 g), stirred for 15 minutes and concentrated. The residue was partitioned between methyl tert-butyl ether (75 mL) and water (20 mL). The methyl tert-butyl ether layer was washed with brine, dried (MgSO₄), filtered, concentrated and chromatographed on silica gel, eluting with 5% methyl tert-butyl ether in heptanes to provide the pure methyl ester, methyl 2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.00 (d, J=8.7 Hz, 1H), 6.67 (d, J=8.5 Hz, 1H), 4.34 (dd, J=2.7, 5.6 Hz, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.51-3.35 (m, 3H), 2.32-2.22 (m, 2H), 2.21-2.09 (m, 2H), 2.05-1.91 (m, 1H), 1.89-1.79 (m, 1H). Methyl 2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate was dissolved in tetrahydrofuran (1.5 mL) and methanol (1.5 mL), treated with 1 M aqueous NaOH (1 mL), stirred at room temperature for 30 minutes, and partitioned between methyl tert-butyl ether (˜75 mL) and 1 M aqueous HCl (15 mL). The methyl tert-butyl ether layer was washed with brine, dried (MgSO₄), filtered, and concentrated to provide the pure title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 7.01 (d, J=8.7 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 4.36 (dd, J=2.5, 5.6 Hz, 1H), 3.84 (s, 3H), 3.52 (dd, J=5.6, 13.8 Hz, 1H), 3.48-3.40 (m, 2H), 2.31-2.23 (m, 2H), 2.19-2.10 (m, 2H), 2.04-1.93 (m, 1H), 1.89-1.81 (m, 1H).

Example I-1021 2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol

A solution of Example I-102A (5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol) (40 mg, 0.266 mmol) in CH₃CN (˜0.5 mL) was treated with N-bromosuccinimide (47.4 mg, 0.266 mmol) and stirred at room temperature for 30 minutes. The mixture was concentrated via a stream of N₂, dissolved in dichloromethane (˜1 mL), and diluted with heptanes. A material formed. The material was removed by filtration and was discarded. The filtrate was concentrated and chromatographed on silica gel, eluting with a gradient of 10% to 30% ethyl acetate in heptanes to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.29-7.25 (m, 1H), 6.62 (dt, J=0.7, 8.9 Hz, 1H), 5.31 (ddd, J=1.8, 4.5, 9.3 Hz, 1H), 3.95 (s, 3H), 3.53 (ddd, J=0.7, 4.6, 14.7 Hz, 1H), 2.95 (ddd, J=0.8, 1.9, 14.7 Hz, 1H), 2.30 (d, J=9.3 Hz, 1H).

Example I-102J 2,7-dibromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene

A solution of Example I-1021 (2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol) (8.35 g, 34.6 mmol), carbon tetrabromide (14.35 g, 43.3 mmol) and triphenylphosphine (16.80 g, 64.1 mmol) in methyl tert-butyl ether (400 mL) was stirred overnight at room temperature. The mixture was diluted with heptanes and the resulting material was removed by filtration. The filtrate was concentrated to dryness and was purified by chromatography on silica gel, eluting with a gradient of 0% to 20% ethyl acetate in heptanes to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.32 (d, J=8.9 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H), 5.45-5.43 (m, 1H), 3.98 (s, 3H), 3.78 (ddd, J=0.8, 4.6, 15.0 Hz, 1H), 3.39 (ddd, J=0.8, 1.7, 14.9 Hz, 1H).

Example I-102K 2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile

A solution of Example I-102J (2,7-dibromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene) (3.26 g, 11.17 mmol) in tetrahydrofuran (74.4 mL) was treated with tetrabutylammonium cyanide (4.50 g, 16.75 mmol) and was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate (250 mL) and water (150 mL). The ethyl acetate layer was washed with saturated aqueous NaHCO₃, washed with brine, dried (MgSO₄), filtered, concentrated and chromatographed on silica gel, eluting with a gradient of 0% to 20% ethyl acetate in heptanes to provide the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 7.33 (dd, J=0.8, 9.0 Hz, 1H), 6.68 (d, J=9.0 Hz, 1H), 4.27 (ddd, J=0.8, 2.7, 5.5 Hz, 1H), 3.92 (s, 3H), 3.57 (ddd, J=0.8, 5.6, 14.3 Hz, 1H), 3.45 (ddd, J=0.8, 2.7, 14.3 Hz, 1H).

Example I-102L 2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile

A mixture of Example I-102K (2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile) (0.17 g, 0.714 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.045 g, 0.056 mmol) in tetrahydrofuran (3.57 mL) was degassed by bubbling a stream of nitrogen through the mixture for 1 minute, treated with 0.5 M cyclobutylzinc bromide in tetrahydrofuran (2.142 mL, 1.071 mmol), stirred for 16 hours at room temperature under nitrogen, and quenched with saturated aqueous ammonium chloride solution (5 mL). The mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated aqueous ammonium chloride, washed with brine, dried (sodium sulfate), filtered, concentrated and chromatographed on silica gel, eluting with a gradient of 0% to 20% ethyl acetate in heptanes to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.05 (d, J=8.6 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 4.30-4.27 (m, 1H), 3.90 (s, 3H), 3.65 (dd, J=5.5, 13.9 Hz, 1H), 3.52 (dd, J=2.7, 14.0 Hz, 1H), 3.42 (p, J=8.8 Hz, 1H), 2.32-2.24 (m, 2H), 2.17-2.06 (m, 2H), 2.06-1.93 (m, 1H), 1.90-1.80 (m, 1H).

Example I-102M 2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

A solution of Example I-102H (2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid) (41 mg, 0.177 mmol) in dichloromethane at 0° C. was treated with oxalyl chloride (77 μl, 0.883 mmol), treated with a catalytic amount of N,N-dimethylformamide, stirred at room temperature for 30 minutes and concentrated with a stream of N₂ for 30 minutes. The residue was dissolved in dichloromethane (˜0.3 mL), cooled to 0° C., treated with naphthalene-1-sulfonamide (47.6 mg, 0.229 mmol), treated with triethylamine (49.2 μL, 0.353 mmol), treated with DMAP (4-dimethylaminopyridine) (2.156 mg, 0.018 mmol), stirred at room temperature for 16 hours, and partitioned between ethyl acetate (35 mL) and 1 M aqueous HCl (15 mL). The ethyl acetate layer was washed with brine, dried (MgSO₄), filtered, concentrated, redissolved in N,N-dimethylformamide (˜1 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1% TFA] to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.74 (s, 1H), 8.64-8.60 (m, 1H), 8.30 (ddd, J=1.1, 4.2, 7.5 Hz, 2H), 8.13 (d, J=8.0 Hz, 1H), 7.78 (ddd, J=1.4, 6.9, 8.6 Hz, 1H), 7.73-7.67 (m, 2H), 6.87 (d, J=8.6 Hz, 1H), 6.51 (d, J=8.6 Hz, 1H), 4.35 (dd, J=2.5, 5.7 Hz, 1H), 3.36-3.22 (m, 1H), 3.29 (s, 3H), 2.81 (dd, J=2.5, 13.9 Hz, 1H), 2.17-2.06 (m, 2H), 2.00-1.81 (m, 4H), 1.75-1.68 (m, 1H). MS (APCI+) m/z 422 (M+H)⁺.

Example I-103 (1R)-4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was added Example I-44 (110 mg, 0.238 mmol) and PEPPSI IPentCl ([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II))) (10.25 mg, 0.012 mmol) in tetrahydrofuran (2 mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 1.5 mL, 0.750 mmol) was added and the reaction was stirred for 16 hours at room temperature. The sample was purified using preparative reverse phase HPLC/MS method TFA7. The material was separated by chiral preparative SFC chromatography using a CHIRALPAK AD-H, column size 21×250 mm, 5 micron, serial Number: ADH0SAMA003-810291, using a concentration of 13 mg/mL in methanol at a flow rate of 56 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound as the first eluent. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 9.10 (dd, J=4.2, 1.6 Hz, 1H), 9.06 (ddd, J=8.8, 1.6, 0.9 Hz, 1H), 8.39 (dt, J=8.4, 1.1 Hz, 1H), 8.36 (dd, J=7.4, 1.3 Hz, 1H), 7.97 (dd, J=8.5, 7.4 Hz, 1H), 7.84 (dd, J=8.8, 4.2 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 6.56 (d, J=8.3 Hz, 1H), 3.91 (dd, J=9.1, 5.7 Hz, 1H), 3.43-3.32 (m, 1H), 3.09 (s, 3H), 2.75-2.61 (m, 2H), 2.32-2.12 (m, 3H), 2.01-1.85 (m, 3H), 1.84-1.67 (m, 2H). MS (APCI+) m/z 437.1 (M+H)⁺.

Example I-104 (1S)-4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-104 was isolated as the second elutent during the preparative SFC separation described in Example I-103. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 9.12-9.01 (m, 2H), 8.40-8.29 (m, 2H), 7.94 (dd, J=8.4, 7.5 Hz, 1H), 7.81 (dd, J=8.8, 4.2 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 3.89 (dd, J=9.1, 5.5 Hz, 1H), 3.46-3.26 (m, 1H), 3.11 (s, 3H), 2.77-2.60 (m, 2H), 2.30-2.12 (m, 3H), 2.04-1.84 (m, 3H), 1.84-1.63 (m, 2H). MS (APCI+) m/z 437.1 (M+H)⁺.

Example I-105 4-bromo-N-(5-hydroxynaphthalene-1-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (54.7 mg, 0.448 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (68.7 mg, 0.358 mmol) were combined in N,N-dimethylacetamide (1 mL). To the suspension was added (S)-4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (60.7 mg, 0.224 mmol). After 30 minutes, 5-hydroxynaphthalene-1-sulfonamide (50 mg, 0.224 mmol) was added. The reaction was heated at 70° C. for 3 days. The mixture was quenched with water (5 mL) and 1 N aqueous citric acid (0.5 mL) to pH ˜4 and was extracted with 4 mL dichloromethane. The solvent was evaporated in vacuo, and the residue was chromatographed using a 12 g silica gel cartridge with 0-5% methanol/dichloromethane over a period of 8 minutes to give crude product which was then purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.47 (s, 1H), 10.60 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.23 (dd, J=7.4, 1.3 Hz, 1H), 8.05 (dd, J=8.7, 0.9 Hz, 1H), 7.57 (ddd, J=10.0, 8.6, 7.5 Hz, 2H), 7.29 (d, J=8.6 Hz, 1H), 7.03 (dd, J=7.7, 0.9 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 4.05 (dd, J=9.2, 5.6 Hz, 1H), 3.18 (s, 3H), 2.74 (td, J=8.3, 7.6, 3.3 Hz, 2H), 2.32-2.21 (m, 1H), 1.80 (dq, J=13.6, 6.6, 6.2 Hz, 1H). MS (APCI+) m/z 476 (M+H⁺).

Example I-106 (7S)-2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

The enantiomers from Example I-102 were separated by Supercritical Fluid Chromatography (SFC) using a 21×250 mm Whelk-O (S,S) chiral column eluting with 20% methanol in liquid CO₂ using a flow rate of 80 mL/minute to provide the title compound as the first peak to elute form the column. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.74 (s, 1H), 8.64-8.60 (m, 1H), 8.30 (ddd, J=1.1, 4.2, 7.5 Hz, 2H), 8.13 (d, J=8.0 Hz, 1H), 7.78 (ddd, J=1.4, 6.9, 8.6 Hz, 1H), 7.73-7.67 (m, 2H), 6.87 (d, J=8.6 Hz, 1H), 6.51 (d, J=8.6 Hz, 1H), 4.35 (dd, J=2.5, 5.7 Hz, 1H), 3.36-3.22 (m, 1H), 3.29 (s, 3H), 2.81 (dd, J=2.5, 13.9 Hz, 1H), 2.17-2.06 (m, 2H), 2.00-1.81 (m, 4H), 1.75-1.68 (m, 1H). MS (APCI+) m/z 422 (M+H)⁺.

Example I-107 (7R)-2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

The enantiomers from Example I-102 were separated by Supercritical Fluid Chromatography (SFC) using a 21×250 mm Whelk-O (S,S) chiral column eluting with 20% methanol in liquid CO₂ using a flow rate of 80 mL/minute to provide the title compound as the second peak to elute from the column. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.74 (s, 1H), 8.64-8.60 (m, 1H), 8.30 (ddd, J=1.1, 4.2, 7.5 Hz, 2H), 8.13 (d, J=8.0 Hz, 1H), 7.78 (ddd, J=1.4, 6.9, 8.6 Hz, 1H), 7.73-7.67 (m, 2H), 6.87 (d, J=8.6 Hz, 1H), 6.51 (d, J=8.6 Hz, 1H), 4.35 (dd, J=2.5, 5.7 Hz, 1H), 3.36-3.22 (m, 1H), 3.29 (s, 3H), 2.81 (dd, J=2.5, 13.9 Hz, 1H), 2.17-2.06 (m, 2H), 2.00-1.81 (m, 4H), 1.75-1.68 (m, 1H). LC/MS (APCI+) m/z 422 (M+H)⁺.

Example I-108 (1R)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-108A 4-methoxy-7-methyl-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A solution of Example I-84B (80 mg, 0.174 mmol), potassium carbonate (96 mg, 0.695 mmol), and trimethylboroxine (0.097 mL, 0.695 mmol) in 1,4-dioxane (1.6 mL) and water (0.3 mL) was degassed with bubbling nitrogen. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (56.8 mg, 0.070 mmol) was added and the mixture was heated at 90° C. with stirring for 16 hours. The mixture was quenched with water (1 mL) and acidified with 1 N aqueous HCl (0.2 mL). The mixture was extracted with dichloromethane (2 mL), and the organic layer was concentrated in vacuo. The resulting residue was chromatographed using a 12 g silica gel cartridge with 0-100% ethyl acetate/heptanes over a period of 10 minutes to give crude product which was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.70 (s, 1H), 8.65 (dd, J=8.6, 1.0 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.27 (dd, J=7.4, 1.3 Hz, 1H), 8.14 (dd, J=8.1, 1.3 Hz, 1H), 7.78 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.63 (m, 2H), 6.72 (d, J=8.2 Hz, 1H), 6.61 (d, J=8.2 Hz, 1H), 3.95 (dd, J=9.3, 4.7 Hz, 1H), 3.66 (s, 3H), 2.65 (t, J=7.4 Hz, 2H), 2.24 (ddt, J=13.0, 9.3, 7.9 Hz, 1H), 1.80 (dtd, J=13.3, 6.8, 4.6 Hz, 1H), 1.44 (s, 3H). MS (APCI+) m/z 396 (M+H⁺).

Example I-108B (1R)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-108A (13 mg) was separated by chiral preparative SFC chromatography using a ChiralPak AD-H column size 21×250 mm, 5 micron, serial Number: ADHSAMA003-810291, using a concentration of 4.0 mg in methanol at a flow rate of 56 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.70 (s, 1H), 8.65 (dd, J=8.6, 1.0 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.27 (dd, J=7.4, 1.3 Hz, 1H), 8.14 (dd, J=8.1, 1.3 Hz, 1H), 7.78 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.63 (m, 2H), 6.72 (d, J=8.2 Hz, 1H), 6.61 (d, J=8.2 Hz, 1H), 3.95 (dd, J=9.3, 4.7 Hz, 1H), 3.66 (s, 3H), 2.65 (t, J=7.4 Hz, 2H), 2.24 (ddt, J=13.0, 9.3, 7.9 Hz, 1H), 1.80 (dtd, J=13.3, 6.8, 4.6 Hz, 1H), 1.44 (s, 3H). MS (APCI+) m/z 396 (M+H⁺). R_(T) (chiral SFC)=6.0 minutes.

Example I-109 (1S)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-108A (13 mg) was separated by chiral preparative SFC chromatography using a ChiralPak AD-H column size 21×250 mm, 5 micron, serial Number: ADHSAMA003-810291, using a concentration of 4.0 mg in methanol at a flow rate of 56 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.70 (s, 1H), 8.65 (dd, J=8.6, 1.0 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.27 (dd, J=7.4, 1.3 Hz, 1H), 8.14 (dd, J=8.1, 1.3 Hz, 1H), 7.78 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.63 (m, 2H), 6.72 (d, J=8.2 Hz, 1H), 6.61 (d, J=8.2 Hz, 1H), 3.95 (dd, J=9.3, 4.7 Hz, 1H), 3.66 (s, 3H), 2.65 (t, J=7.4 Hz, 2H), 2.24 (ddt, J=13.0, 9.3, 7.9 Hz, 1H), 1.80 (dtd, J=13.3, 6.8, 4.6 Hz, 1H), 1.44 (s, 3H). MS (APCI+) m/z 396 (M+H⁺). R_(T) (chiral SFC)=5.1 minutes.

Example I-110

4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide

Example I-110A methyl 4-(3-ethoxy-3-oxopropyl)-2-methoxynicotinate

Methyl 4-chloro-2-methoxynicotinate (1.007 g, 4.99 mmol) (CAS#1256826-55-7) was combined with 2-dicyclohexylphosphino-2′,6′-bis(dimethylamino)-1,1′-biphenyl (0.087 g, 0.200 mmol) and diacetoxypalladium (0.022 g, 0.100 mmol) in toluene (10 mL) under nitrogen and then degassed with nitrogen for 5 minutes. To this mixture was added a solution of (3-ethoxy-3-oxopropyl)zinc(II) bromide (11.99 mL, 5.99 mmol, 0.5 M in tetrahydrofuran), with vigorous stirring. The reaction was stirred at room temperature for 3 hours. The mixture was adsorbed onto silica gel and was chromatographed using a 40 g silica gel cartridge with an ethyl acetate/hexanes solvent system to provide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.12 (dd, J=5.3, 0.8 Hz, 1H), 6.80 (d, J=5.2 Hz, 1H), 4.15 (qd, J=7.2, 0.9 Hz, 2H), 3.97 (d, J=0.8 Hz, 3H), 3.94 (d, J=0.8 Hz, 3H), 2.91 (t, J=7.9 Hz, 2H), 2.74-2.53 (m, 2H), 1.26 (td, J=7.2, 0.9 Hz, 3H). MS (APCI+) m/z 268 (M+H)⁺.

Example I-110B 1-methoxy-5H-cyclopenta[c]pyridin-7(6H)-one

A solution of methyl 4-(3-ethoxy-3-oxopropyl)-2-methoxynicotinate (1.2 g, 4.49 mmol) from Example I-110A in tetrahydrofuran (10 mL) was added to a suspension of 60% sodium hydride (0.898 g, 22.45 mmol) in tetrahydrofuran (10 mL) at room temperature. Once the bubbling subsided, methanol (0.024 mL, 0.593 mmol) was added and the reaction was heated at reflux (block was at 65° C.). The solvent was removed in vacuo. To the material was carefully added ice and water, and the mixture was stirred until it reached room temperature and the bubbling stopped. The reaction was placed in a heating block at 100° C. for 2 hours. The aqueous layer was filtered, cooled and extracted with 2×100 mL of dichloromethane. The combined organics were dried over sodium sulfate and filtered. The solvent was removed in vacuo to provide the title compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 8.29 (d, J=5.2 Hz, 1H), 7.04 (dd, J=5.2, 0.9 Hz, 1H), 4.13 (s, 3H), 3.26-2.98 (m, 2H), 2.83-2.63 (m, 2H). MS (ESI+) m/z 164 (M+H)⁺.

Example I-110C 1-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carbonitrile

In a 50 mL round bottom flask 1-methoxy-5H-cyclopenta[c]pyridin-7(6H)-one (0.339 g, 2.078 mmol) from Example I-110B and TOSMIC (toluenesulfonylmethyl isocyanide, 0.527 g, 2.70 mmol) were dissolved in dimethoxyethane (12 mL). The reaction was cooled to −8° C. (internal temperature) with ice/acetone/dry ice under nitrogen. Potassium tert-butoxide (0.536 g, 4.78 mmol) was added in portions keeping the internal temperature <−5° C. over about an hour. The reaction was allowed to slowly warm to room temperature over two hours. The mixture was quenched with water (30 mL). The aqueous layer was extracted with MTBE (methyl tert-butyl ether, 4×50 mL). The solvent was removed in vacuo and the crude material was chromatographed using a 12 g silica gel cartridge with 1-50% ethyl acetate/hexanes to provide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.09 (dd, J=5.2, 0.7 Hz, 1H), 6.85 (d, J=5.1 Hz, 1H), 4.10 (dd, J=8.8, 5.2 Hz, 1H), 4.04 (s, 3H), 3.22-3.07 (m, 1H), 2.98 (ddd, J=16.9, 8.5, 5.4 Hz, 1H), 2.62-2.41 (m, 2H). MS (ESI+) 175 m/z (M+H⁺).

Example I-110D 1-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid

1-Methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carbonitrile (144 mg, 0.827 mmol) from Example I-110C was dissolved in ethanol (2 mL). A solution of sodium hydroxide (231 mg, 5.79 mmol) in water (2.000 mL) was added, and the resulting mixture was heated at 80° C. for 16 hours. The solvent was reduced in volume and the resulting mixture was acidified with acetic acid (0.379 mL, 6.61 mmol). The material was filtered. The aqueous layer was extracted with 3×15 mL of methyl tert-butyl ether. The combined extracts were dried over sodium sulfate and filtered. The solvent removed in vacuo to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.06 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 4.07 (dd, J=8.9, 4.6 Hz, 1H), 4.01 (s, 3H), 3.19-3.06 (m, 1H), 2.93 (ddd, J=16.7, 8.8, 4.7 Hz, 1H), 2.58-2.38 (m, 2H). MS (ESI+) 194 m/z (M+H)⁺.

Example I-110E 4-bromo-1-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid

To a mixture of 1-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid (Example I-110D, 50 mg, 0.259 mmol) in CS₂ (5 mL) cooled in an ice bath, was added dibromine (0.013 mL, 0.259 mmol) in CS₂ (0.5 mL) slowly. The mixture was stirred overnight, and the solvent was removed, followed by addition of water (2 mL). Methanol (0.5 mL) was added followed by addition of dibromine (0.013 mL, 0.259 mmol). After 10 minutes, the bromine color disappeared. The mixture was purified by chromatography, eluting with ethyl acetate/methanol (9:1) in heptane at a 0-60% gradient to provide the title compound. MS (APCI+) m/z 272.09 (M+H)⁺.

Example I-110F 4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide

A mixture of 4-bromo-1-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid (50 mg, 0.184 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (70.5 mg, 0.368 mmol) and N,N-dimethylpyridin-4-amine (24.69 mg, 0.202 mmol) in dichloromethane (2 mL) was stirred at room temperature for 30 minutes, followed by addition of naphthalene-1-sulfonamide (45.7 mg, 0.221 mmol). The mixture was stirred at room temperature for 2 hours. The crude mixture was purified using reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 90% gradient of acetonitrile in 0.1% aqueous TFA] to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.68 (s, 1H), 8.63 (dd, J=8.6, 1.0 Hz, 1H), 8.37-8.24 (m, 2H), 8.15 (dd, J=8.2, 1.3 Hz, 1H), 8.05 (s, 1H), 7.80 (ddd, J=8.6, 6.9, 1.5 Hz, 1H), 7.74-7.65 (m, 2H), 4.05 (dd, J=9.3, 5.7 Hz, 1H), 2.87-2.70 (m, 2H), 2.34 (dtd, J=13.2, 9.0, 6.1 Hz, 1H), 1.84 (ddt, J=12.6, 8.8, 6.3 Hz, 1H). MS (ESI+) m/z 462.9 (M+H)⁺.

Example I-111 4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide

Into a 4 mL vial was added 4-bromo-1-methoxy-N-(naphthalen-1-ylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide (Example I-110F, 25 mg, 0.054 mmol) and Pd PEPPSI IPentCl ([1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II), (4.43 mg, 5.42 μmol) in tetrahydrofuran (0.5 mL). Cyclobutylzinc(II) bromide (0.325 mL, 0.163 mmol) was added. The reaction was stirred overnight at room temperature. The crude material was directly injected onto a prep HPLC and purified using preparative reverse phase HPLC/MS method TFA8 to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.68-8.59 (m, 1H), 8.36 8.20 (m, 2H), 8.20-8.08 (m, 1H), 7.88-7.77 (m, 1H), 7.77-7.60 (m, 3H), 3.99-3.89 (m, 1H), 3.39 (p, J=8.9 Hz, 1H), 3.22 (s, 3H), 2.70 (t, J=7.9 Hz, 2H), 2.39-2.14 (m, 3H), 2.11-1.63 (m, 5H). MS (APCI+) m/z 437.1 (M+H)⁺.

Example I-112 4-chloro-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide

A mixture of Example I-110F (68 mg, 0.147 mmol) and copper (I) chloride (219 mg, 2.211 mmol) in dimethylacetamide (0.5 mL) was refluxed for overnight at 150° C. The solvent was removed and the residue was purified via chromatography on a 24 g silica gel cartridge, eluting with methanol/ethyl acetate at 0-10% gradient to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.65 (s, 1H), 8.60 (dd, J=8.6, 1.1 Hz, 1H), 8.26 (ddd, J=14.8, 7.9, 1.1 Hz, 2H), 8.11 (dd, J=8.1, 1.3 Hz, 1H), 7.93 (d, J=0.7 Hz, 1H), 7.76 (ddd, J=8.6, 6.9, 1.4 Hz, 1H), 7.72-7.61 (m, 2H), 3.99 (dd, J=9.3, 5.7 Hz, 1H), 3.19 (s, 3H), 2.87-2.70 (m, 2H), 2.32 (dtd, J=13.2, 8.9, 6.1 Hz, 1H), 1.91-1.76 (m, 1H). MS (ESI+) m/z=417.0 (M+H).

Example I-113 4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide Example I-113A methyl 2-methoxy-4-methylnicotinate

Into a 160 mL stainless steel reactor was added 3-bromo-2-methoxy-4-methylpyridine (25 g, 121 mmol), PdCl₂(dppf) [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.771 g, 2.42 mmol), methanol (50 mL) and triethylamine (25.4 mL, 182 mmol). The reactor was degassed with nitrogen gas several times followed by carbon monoxide. The reaction was heated to 100° C. for 10 hours at 60 psi. The reaction was vented and the mixture was filtered. The filtrate was concentrated and was purified by flash column chromatography, eluting with 0 to 30% ethyl acetate in heptanes to provide the title compound. ¹H NMR (501 MHz, Chloroform-d) δ ppm 8.08 (d, J=5.2 Hz, 1H), 6.76 (dd, J=5.3, 0.7 Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 2.32 (d, J=0.6 Hz, 3H). MS (ESI⁺) m/z 452.0 (M+H)⁺.

Example I-113B methyl 1-methoxy-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate

Methyl 2-methoxy-4-methylnicotinate (17.14 g, 95 mmol) in tetrahydrofuran (100 mL) was added over a period of 20 minutes to a solution of lithium diisopropylamide (31.7 mmol), which was freshly prepared from diisobutylamine (18.36 mL, 104 mmol) and butyllithium (41.6 mL, 104 mmol) in tetrahydrofuran (300 mL) at −78° C. The resulting mixture was stirred for 20 minutes. Methyl acrylate (21.51 mL, 236 mmol) was added over 15 minutes. The reaction was stirred at −72° C. for 5 hours. Aqueous 10% acetic acid (199 g, 331 mmol) was added (pH 4-5) and the reaction was allowed to warm to ambient temperature. Ethyl acetate was added (600 mL). The organic layer was washed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered, and concentrated. The crude mixture was purified by flash column chromatography (0 to 40% ethyl acetate in heptanes) to afford the title compound. MS (DCI+) m/z 236.0 (M+H)⁺.

Example I-113C 1-methoxy-6,7-dihydroisoquinolin-8(5H)-one

Methyl 1-methoxy-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate (1.04 g, 4.42 mmol) was dissolved in 6 N aqueous HCl solution and the mixture was stirred at ambient temperature over the weekend. Ethyl acetate (100 mL) was added. The pH was adjusted to ˜10 by addition of 6 M potassium hydroxide. The aqueous layer was extracted twice with ethyl acetate (2×50 mL). The combined organic layers were concentrated to provide the title compound. MS (ESI+) m/z 178.0 (M+H)⁺.

Example I-113D 4-bromo-1-methoxy-6,7-dihydroisoquinolin-8(5H)-one

Dibromine (0.243 mL, 4.74 mmol) in dichloromethane (1 mL) was added to 1-methoxy-6,7-dihydroisoquinolin-8(5H)-one (Example I-113C, 0.700 g, 3.95 mmol) in a mixture of H₂O (5 mL) and methanol (5.00 mL) slowly at room temperature. After the addition, the mixture was stirred for another 30 minutes. Na₂S₃O₇ was added followed by dichloromethane (30 mL). The organic layer was washed with saturated aqueous NaHCO₃ and brine, dried over MgSO₄, and filtered. The filtrate was concentrated and the residue was purified via chromatography on a 24 g silica gel cartridge, eluting with methanol/ethyl acetate 0-20% gradient to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.35 (s, 1H), 4.03 (s, 3H), 2.96 (t, J=6.2 Hz, 2H), 2.67-2.61 (m, 2H), 2.18-2.07 (m, 2H). MS (ESI+) m/z 256.1 (M+H)⁺.

Example I-113E 4-bromo-1-methoxy-5,6,7,8-tetrahydroisoquinoline-8-carbonitrile

To 4-bromo-1-methoxy-6,7-dihydroisoquinolin-8(5H)-one (560 mg, 2.187 mmol) in dimethoxyethane (20 mL) was added 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (555 mg, 2.84 mmol). The mixture was cooled to −15° C. with ice/acetone under a nitrogen atmosphere. Potassium 2-methylpropan-2-olate (613 mg, 5.47 mmol) was added in portions keeping the internal temperature <−10° C. The reaction was stirred at room temperature overnight. The mixture was dissolved in dichloromethane and washed with brine, dried over MgSO₄, filtered and concentrated to provide the crude product which used in next step without further purification.

Example I-113F 4-bromo-1-methoxy-5,6,7,8-tetrahydroisoquinoline-8-carboxylic acid

To 4-bromo-1-methoxy-5,6,7,8-tetrahydroisoquinoline-8-carbonitrile from Example I-113E (600 mg, 2.246 mmol) in ethanol (10 mL) was added sodium hydroxide (1348 mg, 33.7 mmol). The mixture was heated at 140° C. overnight. The solvent was removed and the residue was purified via chromatography on a 40 g silica gel cartridge, eluting with ethyl acetate/methanol (9:1) in heptane at 0-70% gradient to provide the title compound. MS(APCI+) m/z 288 (M+H)⁺.

Example I-113G 4-bromo-1-methoxy-N-(naphthalen-1-ylsulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide

A mixture of Example I-113F (250 mg, 0.874 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine, hydrochloric acid (335 mg, 1.748 mmol) and N,N-dimethylpyridin-4-amine (117 mg, 0.961 mmol) in dichloromethane (4 mL) was stirred at room temperature for 30 minutes. Naphthalene-1-sulfonamide (181 mg, 0.874 mmol) was added. The mixture was stirred for another two hours. The solvent was removed and the residue was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 90% gradient of acetonitrile in 0.1% aqueous TFA] to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.63 (s, 1H), 8.67 (dd, J=8.6, 1.0 Hz, 1H), 8.30 (dt, J=8.3, 1.1 Hz, 1H), 8.25 (dd, J=7.4, 1.2 Hz, 1H), 8.14 (dt, J=8.2, 0.9 Hz, 1H), 8.05 (s, 1H), 7.82 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.75-7.65 (m, 2H), 3.68-3.60 (m, 1H), 3.04 (s, 3H), 2.58-2.37 (m, 2H), 1.84 (dddd, J=13.6, 9.8, 6.6, 2.9 Hz, 1H), 1.79-1.67 (m, 1H), 1.57-1.44 (m, 1H), 1.32 (tdd, J=10.7, 8.4, 5.1 Hz, 1H). MS (ESI+) m/z 477.0 (M+H)⁺.

Example I-114 2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

A solution of Example I-102H (2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid) (37 mg, 0.159 mmol) in CH₂Cl₂ (1 mL) at 0° C. was treated with oxalyl chloride (69.7 μl, 0.796 mmol), treated with 1 drop of N,N-dimethylformamide, stirred at room temperature for 30 minutes and concentrated to dryness with a stream of nitrogen. The residue was dissolved in CH₂Cl₂ (˜0.5 mL), treated with quinoline-5-sulfonamide (43.1 mg, 0.207 mmol), treated with triethylamine (44.4 μl, 0.319 mmol), treated with a catalytic amount of 4-dimethylaminopyridine (2 mg), and stirred at room temperature overnight. The mixture was partitioned between ethyl acetate (75 mL) and 1 M aqueous HCl (10 mL). The ethyl acetate layer was washed with brine, dried (MgSO₄), filtered, concentrated, and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1% TFA]. The material was chromatographed again on silica gel, eluting with a gradient of 25% to 100% [200:1:1 ethyl acetate:HCOOH:H₂O] in heptanes to provide the title compound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s, 1H), 9.08 (dd, J=1.6, 4.2 Hz, 1H), 9.04-9.00 (m, 1H), 8.39-8.35 (m, 2H), 7.95 (t, J=8.0 Hz, 1H), 7.81 (dd, J=4.2, 8.8 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.53 (d, J=8.6 Hz, 1H), 4.33 (dd, J=2.4, 5.7 Hz, 1H), 3.34 (s, 3H), 3.35-3.23 (m, 2H), 2.84 (dd, J=2.5, 13.8 Hz, 1H), 2.12 (tdtd, J=1.7, 3.1, 6.3, 7.5 Hz, 2H), 2.01-1.81 (m, 3H), 1.76-1.68 (m, 1H). LC/MS (APCI+) m/z 423 (M+H)⁺.

Example I-115 (8S)-4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide

4-Bromo-1-methoxy-N-(naphthalen-1-ylsulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide from Example I-113G (190 mg) was separated via chiral SFC, using Regis Whelk-O/Column (size: 21×250 mm, 5 micron; concentration: 20 mg/mL) at a flow rate of 56 mL/minute CO₂, and 14 mL/minute methanol. The first fraction at 9.5 minute was the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.63 (s, 1H), 8.74-8.63 (m, 1H), 8.34-8.21 (m, 2H), 8.14 (dd, J=8.3, 1.3 Hz, 1H), 8.05 (s, 1H), 7.81 (ddd, J=8.5, 6.8, 1.4 Hz, 1H), 7.75-7.63 (m, 2H), 3.64 (dd, J=6.4, 4.8 Hz, 1H), 3.05 (s, 3H), 2.56-2.37 (m, 2H), 1.84 (dddd, J=13.6, 9.8, 6.6, 2.9 Hz, 1H), 1.75 (dq, J=10.5, 3.8 Hz, 1H), 1.59-1.44 (m, 1H), 1.39-1.22 (m, 1H). MS(ESI+) m/z 475.0 (M+H)⁺.

Example I-116 (8R)-4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide

During the chiral separation described in Example I-115, the second fraction at 9.99 minute was the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.63 (s, 1H), 8.71-8.64 (m, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.24 (dd, J=7.5, 1.2 Hz, 1H), 8.14 (dd, J=8.3, 1.3 Hz, 1H), 8.05 (s, 1H), 7.81 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.75-7.62 (m, 2H), 3.70-3.57 (m, 1H), 3.05 (s, 3H), 2.57-2.37 (m, 2H), 1.83 (dtt, J=9.6, 6.3, 2.7 Hz, 1H), 1.79-1.70 (m, 1H), 1.58-1.45 (m, 1H), 1.38-1.24 (m, 1H). MS (ESI+) m/z 475.0 (M+H)⁺.

Example I-117 (1S)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-117A 7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one

A mixture of 7-methoxy-2,3-dihydro-1H-inden-1-one (CAS#34985-41-6, 1 g, 6.17 mmol), trimethyl(trifluoromethyl)silane (1.753 g, 12.33 mmol), silver(I) fluoride (0.196 g, 1.541 mmol) and PhI(OAc)₂ ((diacetoxyiodo)benzene, 3.97 g, 12.33 mmol) in dimethyl sulfoxide (10 mL) was stirred at 45° C. overnight. The reaction mixture was dissolved in dichloromethane (50 mL) and washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1% TFA]. The second fraction was the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.79 (dd, J=8.6, 0.8 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 4.01 (s, 3H), 3.28-3.22 (m, 2H), 2.76-2.68 (m, 2H). MS (ESI+) m/z 231 (M+H)⁺. The first fraction was 7-methoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one. ¹H NMR (500 MHz, Chloroform-d) δ ppm 7.29 (dq, J=1.6, 0.8 Hz, 1H), 6.99 (d, J=1.2 Hz, 1H), 4.00 (s, 3H), 3.19-3.11 (m, 2H), 2.77-2.71 (m, 2H). MS (ESI+) m/z 231 (M+H)⁺.

Example I-117B 7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carbonitrile

In a 50 mL round bottom flask 7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (0.290 g, 1.260 mmol) from Example I-117A and TOSMIC (toluenesulfonylmethyl isocyanide, 0.320 g, 1.638 mmol) were dissolved in dimethoxyethane (12.60 mL). The reaction mixture was cooled to −8° C. (internal temperature) with ice/acetone/dry ice under nitrogen. Solid potassium tert-butoxide (0.325 g, 2.90 mmol) was added in portions keeping the internal temperature below −5° C. about 30 minutes. The reaction was allowed to slowly warm to room temperature and was stirred overnight. The solvent was removed in vacuo and quenched with water (20 mL). The aqueous layer was extracted with ether (3×60 mL). The solvent was removed in vacuo and the crude material was chromatographed using a 25 g silica gel cartridge with 5-50% ethyl acetate/hexanes over 40 minutes to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 7.57 (d, J=8.5 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.14 (dd, J=8.4, 5.3 Hz, 1H), 3.96 (s, 3H), 3.32 (dt, J=16.5, 8.1 Hz, 1H), 3.17 (dtd, J=14.4, 6.5, 3.2 Hz, 1H), 2.66-2.46 (m, 2H). MS (APCI+) m/z 258 (M+H)⁺.

Example I-117C 7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxylic acid

A mixture of Example I-117B (170 mg, 0.705 mmol) and sodium hydroxide (282 mg, 7.05 mmol) in ethanol (6 mL) was stirred at 90° C. overnight. The reaction mixture was purified via chromatography on 12 g cartridge, eluting with ethyl acetate/methanol (9:1) in heptane at 0-70% gradient to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.28 (s, 1H), 7.56 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 3.92 (dd, J=9.4, 4.6 Hz, 1H), 3.83 (s, 3H), 3.14-2.96 (m, 2H), 2.46-2.35 (m, 1H), 2.19 (ddt, J=13.2, 8.6, 4.8 Hz, 1H). MS (APCI+) m/z 258 (M+H)⁺.

Example I-117D (1S)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide

A mixture of 7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxylic acid (36 mg, 0.138 mmol) from Example I-117C and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine, hydrochloric acid (53.0 mg, 0.277 mmol) and N,N-dimethylpyridin-4-amine (18.59 mg, 0.152 mmol) in dichloromethane (1.5 mL) was stirred at room temperature for 30 minutes. 2-Methylquinoline-5-sulfonamide (33.8 mg, 0.152 mmol) was added. The mixture was stirred at room temperature for 2 hours.

The crude product, without work up, was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1% TFA] to provide 7-methoxy-N-((2-methylquinolin-5-yl)sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide. The resulting compound was subjected to chiral SFC separation, using Whelk-O (S,S) column (size: 21×250 mm, 5 micron; concentration: 30 mg/mL) at a flow rate of 49 mL/minute CO₂, and 21 mL/minute methanol. The first fraction was the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 8.94 (d, J=8.8 Hz, 1H), 8.02 (dd, J=7.7, 4.9 Hz, 2H), 7.75-7.68 (m, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 3.73 (dd, J=9.4, 3.9 Hz, 1H), 3.39 (s, 3H), 2.97-2.79 (m, 2H), 2.67 (s, 3H), 2.21 (dq, J=12.7, 8.8 Hz, 1H), 1.96 (ddt, J=12.8, 8.5, 4.2 Hz, 1H). MS (ESI+) m/z 465.0 (M+H)⁺.

Example I-118 (1R)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide

The title compound was the second fraction acquired during the chiral separation of Example I-117D. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 8.95 (d, J=8.8 Hz, 1H), 8.04 (dd, J=7.7, 4.1 Hz, 2H), 7.73 (dd, J=8.4, 7.3 Hz, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 3.76 (dd, J=9.5, 4.1 Hz, 1H), 3.37 (s, 3H), 2.95-2.81 (m, 2H), 2.68 (s, 3H), 2.30-2.17 (m, 1H), 1.94 (ddq, J=13.3, 9.0, 4.5 Hz, 1H). MS (ESI+) m/z 465.0 (M+H)⁺.

Example I-119 4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (16.37 mg, 0.134 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (46.7 mg, 0.244 mmol) were combined in dichloromethane (0.6 mL). To this suspension was added 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (30 mg, 0.122 mmol) from Example I-127C. After 30 minutes, 1,2,3,4-tetrahydroquinoline-8-sulfonamide (25.9 mg, 0.122 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was quenched with 1 N aqueous citric acid (1 mL) to pH ˜4, and was extracted with 2 mL dichloromethane. The solvent was evaporated in vacuo, and the residue was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide the title compound as a trifluoroacetic acid salt. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.82 (s, 1H), 7.41 (dd, J=8.2, 1.6 Hz, 1H), 7.11 (dd, J=7.2, 1.5 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 6.54-6.47 (m, 1H), 6.16 (bs, 1H), 3.90 (dd, J=9.1, 5.6 Hz, 1H), 3.56 (s, 3H), 3.41 (m, 1H), 3.34 (t, J=5.6 Hz, 2H), 2.86-2.64 (m, 4H), 2.31-2.16 (m, 3H), 2.05-1.86 (m, 4H), 1.85-1.70 (m, 3H). MS (APCI⁺) m/z 441 (M+H)⁺.

Example I-120 (8R)-4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide

Example I-120 was prepared and isolated as described in Example I-111, substituting Example 1-116 for Example I-110F. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.66 (d, J=8.5 Hz, 1H), 8.26 (dd, J=19.0, 7.7 Hz, 2H), 8.13 (d, J=8.2 Hz, 1H), 7.84-7.78 (m, 1H), 7.76-7.61 (m, 3H), 3.64-3.57 (m, 1H), 3.48-3.27 (m, 1H), 2.99 (s, 3H), 2.39-2.30 (m, 2H), 2.27-2.13 (m, 2H), 2.04-1.62 (m, 6H), 1.55-1.12 (m, 2H). MS (APCI+) m/z 451.0 (M+H)⁺.

Example I-121 (8S)-4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide

Example I-121 was prepared and isolated as described in Example I-111, substituting Example 1-115 for Example I-110F. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.67 (d, J=8.4 Hz, 1H), 8.25 (dd, J=18.6, 7.6 Hz, 2H), 8.13 (d, J=8.2 Hz, 1H), 7.81 (t, J=7.9 Hz, 1H), 7.75-7.61 (m, 3H), 3.59 (t, J=5.8 Hz, 1H), 3.41-3.32 (m, 1H), 2.99 (s, 3H), 2.43-2.27 (m, 2H), 2.23-2.14 (m, 2H), 1.97-1.60 (m, 6H), 1.47-1.42 (m, 1H), 1.33-1.28 (m, 1H). MS (APCI+) m/z 451.0 (M+H)⁺.

Example I-122 (1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (27.3 mg, 0.223 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (78 mg, 0.406 mmol) were combined in dichloromethane (1 mL). To the suspension was added 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (50 mg, 0.203 mmol) from Example I-127C. After 30 minutes, 1,2,3,4-tetrahydroquinoline-5-sulfonamide (43.1 mg, 0.203 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was quenched with 1 N aqueous citric acid (1 mL) to pH ˜4. The mixture was extracted with 2 mL dichloromethane, and the organic layer was concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide 4-cyclobutyl-7-methoxy-N-((1,2,3,4-tetrahydroquinolin-5-yl)sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide, trifluoroacetic acid. The material was separated by chiral preparative SFC chromatography using an YMC Amylose-C, column size 21×250 mm, 5 micron, using a concentration of 12 mg/mL in methanol at a flow rate of 49 mL/minute CO₂ and UV monitoring at 220 nm to provide the title compound as the trifluoroacetic acid salt. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.69 (s, 1H), 9.10 (dd, J=4.2, 1.6 Hz, 1H), 9.07-8.99 (m, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.34 (dd, J=7.4, 1.2 Hz, 1H), 8.00-7.91 (m, 1H), 7.83 (dd, J=8.8, 4.2 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 6.17 (s, 1H), 4.03 (dd, J=9.2, 5.7 Hz, 1H), 3.10 (s, 3H), 2.77 (t, J=7.5 Hz, 2H), 2.30 (ddt, J=13.0, 9.2, 7.4 Hz, 1H), 1.83 (dtd, J=13.2, 7.4, 5.6 Hz, 1H). MS (APCI+) m/z 441 (M+H)⁺. R_(T) (chiral SFC)=4.34 minutes.

Example I-123 (1S)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (16.37 mg, 0.134 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (46.7 mg, 0.244 mmol) were combined in dichloromethane (0.6 mL). To the suspension was added 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (30 mg, 0.122 mmol) from Example I-127C. After 30 minutes, 1-methyl-1H-benzo[d]imidazole-7-sulfonamide (Example I-133D, 25.7 mg, 0.122 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with 1 N aqueous citric acid (1 mL) to pH ˜4, and extracted with 2 mL dichloromethane. The solvent was evaporated in vacuo, and the residue was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100A AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide 4-cyclobutyl-7-methoxy-N-((l-methyl-1H-benzo[d]imidazol-7-yl)sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide, trifluoroacetic acid. The material was separated by chiral preparative SFC chromatography using an YMC Amylose-C, column size 21×250 mm, 5 micron, using a concentration of 6 mg/mL in methanol at a flow rate of 49 mL/minute CO₂ and UV monitoring at 220 nm to provide the title compound as the trifluoroacetic acid salt. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.49 (s, 1H), 8.46 (s, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H), 4.21 (s, 3H), 4.00 (dd, J=9.1, 5.8 Hz, 1H), 3.40 (p, J=8.7 Hz, 1H), 3.31 (s, 3H), 2.90-2.65 (m, 2H), 2.32 (dtd, J=12.9, 8.9, 5.8 Hz, 1H), 2.21 (tdd, J=8.0, 5.2, 2.8 Hz, 2H), 2.07-1.85 (m, 4H), 1.80-1.70 (m, 1H). MS (APCI+) m/z 440 (M+H⁺). R_(T) (chiral SFC)=3.17 minutes.

Example I-124 7-methoxy-N-(naphthalene-1-sulfonyl)-4-(prop-1-en-2-yl)-2,3-dihydro-1H-indene-1-carboxamide Example I-124A methyl 7-methoxy-1-((naphthalen-1-ylsulfonyl)carbamoyl)-2,3-dihydro-1H-indene-4-carboxylate

To Example I-19C (4-bromo-7-methoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide) (1 g, 2.172 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Heraeus, 0.032 g, 0.043 mmol) in a 50 mL Hast C reactor was added methanol and triethylamine (0.606 mL, 4.34 mmol). The reactor was degassed with argon several times followed by carbon monoxide and the reaction mixture was heated at 100° C. for 16 hours at 60 psi. The reaction mixture was filtered and the solvent was evaporated in vacuo. The residue was purified using a 24 g silica gel cartridge with a gradient of 0-10% methanol/dichloromethane to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.59 (s, 1H), 8.66 (dd, J=8.7, 1.1 Hz, 1H), 8.30 (d, J=8.2 Hz, 1H), 8.26 (dd, J=7.4, 1.3 Hz, 1H), 8.17-8.10 (m, 1H), 7.84-7.78 (m, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.74-7.71 (m, 1H), 7.68 (dd, J=8.2, 7.4 Hz, 1H), 6.73 (d, J=8.7 Hz, 1H), 3.95 (dd, J=9.4, 5.6 Hz, 1H), 3.74 (s, 3H), 3.16 (s, 3H), 3.06 (t, J=7.6 Hz, 2H), 2.35-2.21 (m, 1H), 1.80 (td, J=13.1, 7.2 Hz, 1H). MS (APCI+) m/z 440 (M+H⁺).

Example I-124B 7-methoxy-N-(naphthalene-1-sulfonyl)-4-(prop-1-en-2-yl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of methyl 7-methoxy-1-((naphthalen-1-ylsulfonyl)carbamoyl)-2,3-dihydro-1H-indene-4-carboxylate (100 mg, 0.228 mmol) from Example I-124A in tetrahydrofuran (1.5 mL) at 25° C. was added dropwise methyl magnesium bromide in diethyl ether (1.517 mL, 4.55 mmol). The reaction mixture was stirred for 60 minutes, quenched with 1 N aqueous HCl (3 mL), and extracted with 10 mL dichloromethane. The solvent was evaporated in vacuo and the resulting residue was purified on a 12 g silica gel cartridge with a gradient of 0-100% ethyl acetate/hexane over a period of 17 minutes to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.48 (s, 1H), 8.63 (d, J=1.0 Hz, 1H), 8.26 (d, J=8.1 Hz, 1H), 8.23 (dd, J=7.4, 1.2 Hz, 1H), 8.12-8.08 (m, 1H), 7.77 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.70-7.67 (m, 1H), 7.65 (dd, J=8.2, 7.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 5.04 (t, J=1.7 Hz, 1H), 4.82 (d, J=1.2 Hz, 1H), 3.91 (dd, J=9.0, 5.7 Hz, 1H), 3.07 (s, 3H), 2.77 (t, J=7.4 Hz, 2H), 2.24-2.10 (m, 1H), 1.93 (d, J=0.6 Hz, 3H), 1.74 (ddt, J=13.0, 7.7, 6.3 Hz, 1H). MS (ESI+) m/z 422 (M+H)⁺.

Example I-125 4-(2-hydroxypropan-2-yl)-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of methyl 7-methoxy-1-((naphthalen-1-ylsulfonyl)carbamoyl)-2,3-dihydro-1H-indene-4-carboxylate (60 mg, 0.137 mmol) from Example I-124A in 2-methyl tetrahydrofuran (1.5 mL) at 25° C. was added dropwise methylmagnesium bromide in diethyl ether (0.910 mL, 2.73 mmol). The reaction mixture was stirred for 30 minutes, quenched with 2 mL saturated aqueous ammonium chloride, and extracted with ethyl acetate. The solvent was evaporated in vacuo and the resulting residue was purified on 2×0.25 mm silica gel plate eluting with 70% ethyl acetate/heptanes. The material was repurified on a 2×0.25 mm silica gel plate eluting with 3% methanol/dichloromethane to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.48 (s, 1H), 8.68 (dd, J=8.6, 1.0 Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.26 (dd, J=7.5, 1.2 Hz, 1H), 8.16-8.11 (m, 1H), 7.84-7.77 (m, 1H), 7.74-7.70 (m, 1H), 7.67 (dd, J=8.1, 7.4 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.50 (d, J=8.5 Hz, 1H), 4.70 (s, 1H), 3.88 (dd, J=9.0, 5.9 Hz, 1H), 3.07 (s, 3H), 3.04-2.87 (m, 2H), 2.17 (dtd, J=12.7, 8.6, 6.2 Hz, 1H), 1.74 (ddt, J=12.5, 8.5, 6.2 Hz, 1H), 1.34 (d, J=1.5 Hz, 6H). MS (ESI+) m/z 440 (M+H)⁺.

Example I-126 (1R)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (16.37 mg, 0.134 mmol), and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (46.7 mg, 0.244 mmol) were combined in dichloromethane (0.6 mL). To the mixture was added 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (30 mg, 0.122 mmol) from Example I-127C. After 30 minutes, 1-methyl-1H-benzo[d]imidazole-7-sulfonamide (Example I-133D, 25.7 mg, 0.122 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was quenched with 1 N aqueous citric acid (1 mL) to pH ˜4, and was extracted with 2 mL dichloromethane. The solvent was evaporated in vacuo. The residue was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide 4-cyclobutyl-7-methoxy-N-((1-methyl-1H-benzo[d]imidazol-7-yl)sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide, trifluoroacetic acid salt. The material was separated by chiral preparative SFC chromatography using an YMC Amylose-C, column size 21×250 mm, 5 micron, and using a concentration of 6 mg/mL in methanol at a flow rate of 49 mL/minute CO₂ and UV monitoring at 220 nm to provide the title compound as the trifluoroacetic acid salt. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.49 (s, 1H), 8.46 (s, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H), 4.21 (s, 3H), 4.00 (dd, J=9.1, 5.8 Hz, 1H), 3.40 (p, J=8.7 Hz, 1H), 3.31 (s, 3H), 2.90-2.65 (m, 2H), 2.32 (dtd, J=12.9, 8.9, 5.8 Hz, 1H), 2.21 (tdd, J=8.0, 5.2, 2.8 Hz, 2H), 2.07-1.85 (m, 4H), 1.80-1.70 (m, 1H). MS (APCI+) m/z 440 (M+H⁺). R_(T) (chiral SFC)=5.16 minutes.

Example I-127 (1S)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-127A 4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonitrile

In a 50 mL round bottom flask, 4-bromo-7-methoxy-2,3-dihydro-1H-inden-1-one (0.977 g, 4.05 mmol) (CAS#5411-61-0) and TOSMIC (toluenesulfonylmethyl isocyanide, 1.029 g, 5.27 mmol) were dissolved in dimethoxyethane (20 mL). The reaction was cooled to −8° C. (internal temperature) with ice/acetone/dry ice under nitrogen. Solid potassium tert-butoxide (1.046 g, 9.32 mmol) was added in portions, keeping the internal temperature <−5° C. over about an hour. The reaction mixture was allowed to slowly warm to room temperature overnight. The solvent was removed in vacuo and the crude material was quenched with water (30 mL). The aqueous layer was extracted with diethyl ether (4×50 mL) and the organics were washed with brine and dried (Na₂SO₄). After filtration, the solvent was removed in vacuo and the crude material was chromatographed using a 40 g silica gel cartridge with 1-50% ethyl acetate/hexanes to provide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.40 (dd, J=8.7, 0.7 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 4.23-4.17 (m, 1H), 3.89 (s, 3H), 3.24-3.11 (m, 1H), 3.06-2.95 (m, 1H), 2.61-2.42 (m, 2H).

Example I-127B 4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid

4-Bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonitrile (1.3 g, 5.16 mmol) from Example I-127A was dissolved in ethanol (17.2 mL). A solution of sodium hydroxide (2.062 g, 51.6 mmol) in 17.2 mL of water was added, and the resulting mixture was heated at 80° C. After 16 hours, the reaction was cooled in an ice bath and acidified with 6 M aqueous HCl (11 mL) to pH ˜2. The resulting precipitate was filtered and washed with water to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 7.38 (d, J=8.6 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 3.97 (dd, J=9.4, 4.5 Hz, 1H), 3.74 (s, 3H), 2.95 (ddd, J=16.1, 8.7, 7.2 Hz, 1H), 2.85 (ddd, J=16.3, 9.0, 4.8 Hz, 1H), 2.39 (dtd, J=13.1, 9.2, 7.2 Hz, 1H), 2.15 (tt, J=8.6, 4.5 Hz, 1H). MS (ESI+) m/z 271 (M+H+)⁺-Br doublet.

Example I-127C 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid

A solution of 4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (100 mg, 0.369 mmol) from Example I-127B and (dichloro[4,5-dichloro-1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (Peppsi-IPent-Cl, 27.0 mg, 0.037 mmol) in tetrahydrofuran (1 mL) was treated with 0.5 M cyclobutylzinc bromide in tetrahydrofuran (3 mL, 1.500 mmol) and the reaction was stirred at room temperature under nitrogen overnight. The solvent was reduced in volume to about half and the reaction was quenched with 1 mL of saturated aqueous ammonium chloride. The aqueous layer was removed by pipette (pH neutral) and the organics were directly applied to a 12 g silica gel cartridge and chromatographed with an ethyl acetate/ethanol/heptanes solvent system to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 9.73 (s, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H), 4.13 (dd, J=9.2, 3.4 Hz, 1H), 3.91 (s, 3H), 3.52 (p, J=8.9, 8.4 Hz, 1H), 3.01 (dt, J=16.5, 8.5 Hz, 1H), 2.84 (ddd, J=16.1, 9.1, 3.6 Hz, 1H), 2.60 (ddt, J=13.2, 8.6, 3.5 Hz, 1H), 2.40-2.27 (m, 3H), 2.17-1.94 (m, 3H), 1.90-1.79 (m, 1H). MS (APCI+) m/z 247 (M+H⁺).

Example I-127D 2-methylquinoline-5-sulfonamide

Thionyl chloride (2.1 mL, 28.8 mmol) was added dropwise to water at 5° C. and was allowed to warm to room temperature and stir overnight. To the mixture was added copper(I) chloride (0.01 g, 0.101 mmol) and the reaction was cooled to 0° C. 2-Methylquinolin-5-amine (0.978 g, 6.18 mmol) was added portionwise to a cooled (ice bath) solution of concentrated aqueous HCl (6.75 mL). To the cooled (−5° C.) solution was added a solution of sodium nitrite (0.5 g, 7.25 mmol) in water (2 mL) dropwise. After the addition, the resulting mixture was added slowly to the cooled thionyl chloride/CuCl mixture at −5° C. The mixture was stirred at 0° C. for 2 hours and was filtered. The solvent was reduced in vacuo and filtered into a cooled (ice bath) solution of 100 mL ammonium hydroxide with rapid stirring. The ammonium hydroxide solution was then filtered again and the solvent was removed in vacuo. The material was taken up in water (25 mL) and filtered, and the material was washed with water (2×15 mL) to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.86 (dd, J=8.9, 0.9 Hz, 1H), 8.11 (dt, J=8.5, 1.0 Hz, 1H), 8.07 (dd, J=7.5, 1.2 Hz, 1H), 7.79 (dd, J=8.4, 7.4 Hz, 1H), 7.70 (s, 2H), 7.57 (d, J=8.8 Hz, 1H), 2.66 (s, 3H). MS (ESI+) m/z 223 (M+H⁺).

Example I-127E (1S)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A suspension of 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (46 mg, 0.187 mmol) form Example I-127C, N,N-dimethylpyridin-4-amine (25.10 mg, 0.205 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (71.6 mg, 0.374 mmol) in dichloromethane (2 mL) was stirred for 30 minutes at room temperature, and treated with 2-methylquinoline-5-sulfonamide (45.7 mg, 0.205 mmol) from Example I-127D. The reaction was stirred at room temperature overnight. The solvent was reduced in volume and the organics were directly applied to a 12 g silica gel cartridge and chromatographed with an ethyl acetate/methanol solvent system to provide 4-cyclobutyl-7-methoxy-N-((2-methylquinolin-5-yl)sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide, which was separated by chiral preparative SFC chromatography using a ChiralCel® OJ-H, column size 21×250 mm, 5 micron, serial Number: OJH0SA0D002-011121, using a concentration of 12 mg/mL in methanol at a flow rate of 50 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, Chloroform-d) δ ppm 9.86 (s, 1H), 8.69 (dd, J=8.9, 0.9 Hz, 1H), 8.41 (dd, J=7.5, 1.2 Hz, 1H), 8.26 (dt, J=8.6, 1.0 Hz, 1H), 7.77 (dd, J=8.5, 7.5 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 4.03 (s, 3H), 3.97 (dd, J=8.9, 1.5 Hz, 1H), 3.47-3.36 (m, 1H), 2.77 (s, 3H), 2.72-2.65 (m, 2H), 2.63-2.53 (m, 1H), 2.36-2.27 (m, 1H), 2.27-2.19 (m, 1H), 2.15-1.91 (m, 4H), 1.90-1.78 (m, 1H). MS (APCI+) m/z 451 (M+H⁺). R_(T) (chiral SFC)=2.87 minutes.

Example I-128 (1R)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A suspension of 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (46 mg, 0.187 mmol) from Example I-127C, N,N-dimethylpyridin-4-amine (25.10 mg, 0.205 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (71.6 mg, 0.374 mmol) in dichloromethane (2 mL) was stirred for 30 minutes at room temperature, and treated with 2-methylquinoline-5-sulfonamide (45.7 mg, 0.205 mmol) from Example I-127D. The reaction was stirred at room temperature overnight. The solvent was reduced in volume and the organics were directly applied to a 12 g silica gel cartridge and chromatographed with an ethyl acetate/methanol solvent system to provide 4-cyclobutyl-7-methoxy-N-((2-methylquinolin-5-yl)sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide which was separated by chiral preparative SFC chromatography using a ChiralCel® OJ-H, column size 21×250 mm, 5 micron, serial Number: OJH0SA0D002-011121, using a concentration of 12 mg/mL in methanol at a flow rate of 50 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (501 MHz, Chloroform-d) δ ppm 9.86 (s, 1H), 8.69 (dd, J=8.9, 0.9 Hz, 1H), 8.41 (dd, J=7.5, 1.2 Hz, 1H), 8.26 (dt, J=8.6, 1.0 Hz, 1H), 7.77 (dd, J=8.5, 7.5 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 4.03 (s, 3H), 3.97 (dd, J=8.9, 1.5 Hz, 1H), 3.47-3.36 (m, 1H), 2.77 (s, 3H), 2.72-2.65 (m, 2H), 2.63-2.53 (m, 1H), 2.36-2.27 (m, 1H), 2.27-2.19 (m, 1H), 2.15-1.91 (m, 4H), 1.90-1.78 (m, 1H). MS (APCI+) m/z 451 (M+H⁺). R_(T) (chiral SFC)=3.37 minutes.

Example I-129 (1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (27.3 mg, 0.223 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (78 mg, 0.406 mmol) were combined in dichloromethane (1 mL). To the suspension was added 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (50 mg, 0.203 mmol) from Example I-127C. After 30 minutes, 1,2,3,4-tetrahydroquinoline-5-sulfonamide (43.1 mg, 0.203 mmol) (CAS#1155515-51-7) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with 1 N aqueous citric acid (1 mL) to pH ˜4 and was extracted with 2 mL dichloromethane. The solvent was evaporated in vacuo, and the residue was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide 4-cyclobutyl-7-methoxy-N-((1,2,3,4-tetrahydroquinolin-5-yl)sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide, trifluoroacetic acid salt. The material was separated by chiral preparative SFC chromatography using an YMC Amylose-C, column size 21×250 mm, 5 micron, using a concentration of 12 mg/mL in methanol at a flow rate of 49 mL/minute CO₂ and UV monitoring at 220 nm to provide the title compound as a trifluoroacetic acid salt. ¹H NM R (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.69 (s, 1H), 9.10 (dd, J=4.2, 1.6 Hz, 1H), 9.07-8.99 (m, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.34 (dd, J=7.4, 1.2 Hz, 1H), 8.00-7.91 (m, 1H), 7.83 (dd, J=8.8, 4.2 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 6.17 (s, 1H), 4.03 (dd, J=9.2, 5.7 Hz, 1H), 3.10 (s, 3H), 2.77 (t, J=7.5 Hz, 2H), 2.30 (ddt, J=13.0, 9.2, 7.4 Hz, 1H), 1.83 (dtd, J=13.2, 7.4, 5.6 Hz, 1H). MS (APCI+) m/z 441 (M+H)⁺. R_(T) (chiral SFC)=6.66 minutes.

Example I-130 (1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-130A 1,2,3,4-tetrahydroquinoline-8-sulfonamide

Quinoline-8-sulfonamide (101.1 mg, 0.486 mmol) and ethanol (2 mL) were added to 20% Pd(OH)₂/C, wet (22 mg, 0.080 mmol) in a 20 mL Barnstead Hast C. The mixture was stirred at 50 psi hydrogen and 65° C. overnight. The reaction was filtered and the solvent was removed in vacuo to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 7.36 (dd, J=8.0, 1.6 Hz, 1H), 7.14 (s, 2H), 7.01 (dd, J=7.3, 1.5 Hz, 1H), 6.46 (dd, J=7.9, 7.3 Hz, 1H), 5.89 (s, 1H), 3.33-3.30 (m, 2H), 2.70 (t, J=6.3 Hz, 2H), 1.93-1.60 (m, 2H). MS (APCI+) m/z 213 (M+H⁺).

Example I-130B (1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (16.37 mg, 0.134 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (46.7 mg, 0.244 mmol) were combined in dichloromethane (0.6 mL). To the suspension was added 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (30 mg, 0.122 mmol) from Example I-127C. After 30 minutes, 1,2,3,4-tetrahydroquinoline-8-sulfonamide (25.9 mg, 0.122 mmol) from Example I-130A was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was quenched with 1 N aqueous citric acid (1 mL) to pH ˜4 and extracted with 2 mL dichloromethane. The solvent was evaporated in vacuo, and the residue was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide 4-cyclobutyl-7-methoxy-N-((1,2,3,4-tetrahydroquinolin-8-yl)sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide, trifluoroacetic acid. The material was separated by chiral preparative SFC chromatography using a YMC Amylose-C, column size 21×250 mm, 5 micron, and a concentration of 6 mg/mL in methanol at a flow rate of 1 mL/minute CO₂ and UV monitoring at 220 nm to provide (1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide as a trifluoroacetic acid salt. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.70 (s, 1H), 8.65 (dd, J=8.6, 1.0 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.27 (dd, J=7.4, 1.3 Hz, 1H), 8.14 (dd, J=8.1, 1.3 Hz, 1H), 7.78 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.63 (m, 2H), 6.72 (d, J=8.2 Hz, 1H), 6.61 (d, J=8.2 Hz, 1H), 3.95 (dd, J=9.3, 4.7 Hz, 1H), 3.66 (s, 3H), 2.65 (t, J=7.4 Hz, 2H), 2.24 (ddt, J=13.0, 9.3, 7.9 Hz, 1H), 1.80 (dtd, J=13.3, 6.8, 4.6 Hz, 1H), 1.44 (s, 3H). MS (APCI+) m/z 396 (M+H)⁺. R_(T) (chiral SFC)=9.36 minutes.

Example I-131 (1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

N,N-Dimethylpyridin-4-amine (16.37 mg, 0.134 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (46.7 mg, 0.244 mmol) were combined in dichloromethane (0.6 mL). To the suspension was added 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (30 mg, 0.122 mmol) from Example I-127C. After 30 minutes, 1,2,3,4-tetrahydroquinoline-8-sulfonamide (25.9 mg, 0.122 mmol) from Example I-130A was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was quenched with 1 N aqueous citric acid (1 mL) to pH ˜4, and was extracted with 2 mL dichloromethane. The solvent was evaporated in vacuo, and the residue was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide 4-cyclobutyl-7-methoxy-N-((1,2,3,4-tetrahydroquinolin-8-yl)sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide, trifluoroacetic acid salt. The material was separated by chiral preparative SFC chromatography using a YMC Amylose-C, column size 21×250 mm, 5 micron, using a concentration of 6 mg/mL in methanol at a flow rate of 50 mL/minute CO₂ and UV monitoring at 220 nm to provide (1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide as a trifluoroacetic acid salt. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 12.70 (s, 1H), 8.65 (dd, J=8.6, 1.0 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.27 (dd, J=7.4, 1.3 Hz, 1H), 8.14 (dd, J=8.1, 1.3 Hz, 1H), 7.78 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.63 (m, 2H), 6.72 (d, J=8.2 Hz, 1H), 6.61 (d, J=8.2 Hz, 1H), 3.95 (dd, J=9.3, 4.7 Hz, 1H), 3.66 (s, 3H), 2.65 (t, J=7.4 Hz, 2H), 2.24 (ddt, J=13.0, 9.3, 7.9 Hz, 1H), 1.80 (dtd, J=13.3, 6.8, 4.6 Hz, 1H), 1.44 (s, 3H). MS (APCI+) m/z 396 (M+H)⁺. R_(T) (chiral SFC)=10.40 minutes.

Example I-132 2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

Into a 4 mL vial was added 2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (Example 102H, 60.0 mg, 0.258 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (99 mg, 0.516 mmol), and N,N-dimethylpyridin-4-amine (34.7 mg, 0.284 mmol) in dichloromethane (1 mL). 1-Methyl-1H-indazole-7-sulfonamide (Example I-97A, 60 mg, 0.284 mmol) was added. The reaction was stirred for 2 hours at room temperature. The solvent removed under a stream of nitrogen. The residue was reconstituted in methanol and purified using preparative reverse phase HPLC/MS method TFA8 to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.32 (s, 1H), 8.17 (dd, J=7.9, 1.2 Hz, 1H), 8.10 (dd, J=7.5, 1.1 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 6.59 (d, J=8.6 Hz, 1H), 4.43 (s, 3H), 4.36 (dd, J=5.4, 2.4 Hz, 1H), 3.49 (s, 3H), 3.42-3.27 (m, 2H), 3.01 (dd, J=13.8, 2.4 Hz, 1H), 2.22-2.11 (m, 2H), 2.06-1.94 (m, 2H), 1.94-1.84 (m, 1H), 1.81-1.71 (m, 1H). MS (APCI+) m/z 426.1 (M+H)⁺.

Example I-133 4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-133A 2-bromo-N-methyl-6-nitroaniline

1-Bromo-2-fluoro-3-nitrobenzene (10.00 g, 45.5 mmol) was dissolved in a solution of methanamine (68.2 mL, 136 mmol) in tetrahydrofuran (2 M). The mixture was heated to 60° C. in a sealed flask and was allowed to stir for 18 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (200 mL) and washed sequentially with water (30 mL) and brine (30 mL), then dried over Na₂SO₄, filtered and concentrated to provide the title compound. MS (ESI+) m/z 231.1 (M+H)⁺.

Example I-133B 7-bromo-1-methyl-1H-benzo[d]imidazole

A suspension of iron (10.15 g, 182 mmol) in a solution of 2-bromo-N-methyl-6-nitroaniline (7.00 g, 30.3 mmol) and ammonium chloride (9.72 g, 182 mmol) in isopropyl alcohol (60 mL) and formic acid (60 mL, 1564 mmol) was stirred at 90° C. under N₂ for 16 hours. The mixture was diluted with CH₂Cl₂ (200 mL) and filtered. The filtrate was concentrated to dryness and the resulting residue was partitioned between CH₂Cl₂ (100 mL) and saturated aqueous NaHCO₃ (100 mL). The aqueous layer was extracted with CH₂Cl₂ (3×100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (10% methanol in CH₂Cl₂) to provide the title compound. MS (ESI+) m/z 211.1 (M+H)⁺.

Example I-133C 1-methyl-1H-benzo[d]imidazole-7-sulfonyl fluoride

A 20 mL microwave vial was charged with DABSO (1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct, 569 mg, 2.369 mmol), PdCl₂(AmPhos)₂ (bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 84 mg, 0.118 mmol) and 7-bromo-1-methyl-1H-benzo[d]imidazole (500 mg, 2.369 mmol). A mixture of N-cyclohexyl-N-methylcyclohexanamine (1.531 mL, 7.11 mmol) in anhydrous isopropyl alcohol (11 mL) was added. The vial was sealed with a Teflon cap, sparged for 5 minutes with N₂ and subjected to microwave conditions at 110° C. for 2.5 hours. After cooling to room temperature, N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (1121 mg, 3.55 mmol) was added and the reaction mixture was stirred for 2 hours until completion. The reaction mixture was diluted with H₂O (30 mL) and extracted with ethyl acetate (2×100 mL). The organics were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (50%-80% ethyl acetate in petroleum) to provide the title compound. MS (ESI+) m/z 215.1 (M+H)⁺.

Example I-133D 1-methyl-1H-benzo[d]imidazole-7-sulfonamide

Ammonium hydroxide (65 mL, 1669 mmol) in a round bottomed flask was cooled to 0° C. 1-Methyl-1H-benzo[d]imidazole-7-sulfonyl fluoride (1.250 g, 5.84 mmol) was added, and the mixture was stirred at 0° C. for 5 hours, and stirred at room temperature for 16 hours After completion, the mixture was added dropwise into an aqueous 1 N HCl solution at 0° C., adjusting the pH to within 4-5. The acidic solution was purified by combi-flash chromatography (mobile phase: 5% methanol (B) in H₂O (0.04% TFA) (A), time: 15-20 minutes) to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.75 (s, 1H), 7.98 (s, 2H), 7.98 (d, J=7.6 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 4.19 (s, 3H). MS (ESI+) m/z 212.1 (M+H)⁺.

Example I-133E 4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-133E was prepared and isolated as described in Example I-132, substituting 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (Example I-127C) for Example I-102H, and 1-methyl-1H-benzo[d]imidazole-7-sulfonamide for Example I-97A. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.48 (s, 1H), 8.04 (dd, J=8.1, 1.1 Hz, 1H), 7.93 (dd, J=7.9, 1.0 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.64 (d, J=8.3 Hz, 1H), 4.22 (s, 3H), 4.00 (dd, J=9.0, 5.8 Hz, 1H), 3.46-3.36 (m, 1H), 3.31 (s, 3H), 2.86-2.68 (m, 2H), 2.39-2.28 (m, 1H), 2.26-2.14 (m, 2H), 2.03-1.86 (m, 4H), 1.81-1.69 (m, 1H). MS (APCI+) m/z 440.1 (M+H)⁺.

Example I-134 2-cyclobutyl-5-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

Example I-134 was isolated as described in Example I-132, substituting 1-methyl-1H-benzo[d]imidazole-7-sulfonamide for 1-methyl-1H-indazole-7-sulfonamide. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.43 (s, 1H), 8.04 (dd, J=8.1, 1.1 Hz, 1H), 7.94 (dd, J=7.9, 1.1 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 6.95 (d, J=8.6 Hz, 1H), 6.61 (d, J=8.6 Hz, 1H), 4.37 (dd, J=5.4, 2.4 Hz, 1H), 4.21 (s, 3H), 3.53 (s, 3H), 3.42-3.27 (m, 2H), 3.05 (dd, J=13.9, 2.4 Hz, 1H), 2.22-2.12 (m, 2H), 2.04-1.84 (m, 3H), 1.81-1.71 (m, 1H). MS (APCI+) m/z 442.0 (M+H)⁺.

Example I-135 4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-135A methyl 4-sulfamoylpyrazolo[1,5-a]pyridine-3-carboxylate

n-Butyllithium (0.251 g, 3.92 mmol) (2.5 M in tetrahydrofuran) and dibutylmagnesium (1.629 g, 11.76 mmol) (1.0 M in heptane) were charged into a nitrogen filled three-necked flask at room temperature. A mixture of methyl 4-bromopyrazolo[1,5-a]pyridine-3-carboxylate (2.000 g, 7.84 mmol) in tetrahydrofuran (25 mL) was added dropwise to the n-Bu₃MgLi solution at −25° C. and the mixture was stirred at −10° C. for 1 hour. The resulting mixture was added to a solution of sulfuryl dichloride (1.587 mL, 19.60 mmol) in toluene (20 mL) at −10° C. and the mixture was stirred for 20 minutes at −10° C. The reaction mixture was concentrated. Ammonium hydroxide (15 mL, 7.84 mmol) was added to the crude material at room temperature, and the mixture was stirred for 15 minutes. After completion, the mixture was concentrated. The crude material was purified by silica gel chromatography (25%-40% ethyl acetate in petroleum). The resultant material was purified again by Prep-HPLC on a Gilson 281(PHG013) with Boston pHlex ODS column (21.2×250 mm, 10 μm), using a gradient of acetonitrile (B) and 0.05% trifluoroacetic acid in water (A) at 35-55% B in 10 minutes with stop at 15 minutes, at a flow rate of 25 mL/minute to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.70 (dd, J=6.8, 1.0 Hz, 1H), 8.50 (s, 1H), 8.25 (dd, J=7.4, 1.0 Hz, 1H), 7.08 (t, J=7.1 Hz, 1H), 6.60 (s, 2H), 3.96 (s, 3H). MS (ESI+) m/z 256.1 (M+H)⁺.

Example I-135B pyrazolo[1,5-a]pyridine-4-sulfonamide

Methyl 4-sulfamoylpyrazolo[1,5-a]pyridine-3-carboxylate (0.535 g, 1.258 mmol) was heated in H₂SO₄ (12.33 g, 62.9 mmol) at 90° C. for 10 hours. After cooling, the reaction mixture was neutralized with 4 N aqueous NaOH to pH 5. The mixture was extracted with ethyl acetate (2×100 mL) and washed with brine (30 mL). The organics were dried over Na₂SO₄ (5 g), filtered, and concentrated. The residue was purified by Combi-Flash chromatography (H₂O (0.01% TFA) (A)/methanol (B), gradient from 5-25% of B at 10 minutes-25 minutes to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.92 (d, J=7.2, 1H), 8.18 (s, 1H), 7.74 (s, 2H), 7.70 (d, J=6.8, 1H), 7.03 (t, J=7.0, 1H), 6.99 (s, 1H). MS (ESI+) m/z 198.7 (M+H)⁺.

Example 135C 4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-135C was prepared and isolated as described in Example I-132, substituting Example I-127C for Example I-102H, and pyrazolo[1,5-a]pyridine-4-sulfonamide (Example I-135B) for Example I-97A. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.98 (d, J=7.0 Hz, 1H), 8.26 (d, J=2.3 Hz, 1H), 7.87 (d, J=7.2 Hz, 1H), 7.09 (t, J=7.1 Hz, 1H), 7.05-6.98 (m, 2H), 6.61 (d, J=8.4 Hz, 1H), 3.92 (dd, J=9.1, 5.7 Hz, 1H), 3.40 (p, J=8.6 Hz, 1H), 3.24 (s, 3H), 2.79-2.63 (m, 2H), 2.31-2.16 (m, 3H), 2.03-1.78 (m, 4H), 1.79-1.70 (m, 1H). MS (APCI+) m/z 426.1 (M+H)⁺.

Example I-136 2-cyclobutyl-5-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

Example I-136 was prepared and isolated as described in Example I-132, substituting pyrazolo[1,5-a]pyridine-4-sulfonamide (Example I-135B) for Example I-97A. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.99 (dt, J=6.9, 1.0 Hz, 1H), 8.29-8.24 (m, 1H), 7.92 (dd, J=7.2, 1.1 Hz, 1H), 7.11 (t, J=7.1 Hz, 1H), 7.00-6.95 (m, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 4.34 (dd, J=5.8, 2.4 Hz, 1H), 3.43 (s, 3H), 3.39 (dd, J=13.9, 5.7 Hz, 1H), 3.31 (p, J=8.8, 8.3 Hz, 1H), 2.90 (dd, J=13.9, 2.5 Hz, 1H), 2.20-2.10 (m, 2H), 2.04-1.83 (m, 3H), 1.80-1.70 (m, 1H). MS (APCI+) m/z 412.1 (M+H)⁺.

Example I-137 2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

Example I-137 was prepared as described in Example I-132, substituting 1,2,3,4-tetrahydroquinoline-5-sulfonamide for Example I-97A. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 7.09 (dd, J=7.8, 1.4 Hz, 1H), 7.03 (t, J=7.9 Hz, 1H), 6.97 (d, J=8.6 Hz, 1H), 6.73 (dd, J=7.9, 1.4 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 4.37 (dd, J=5.7, 2.3 Hz, 1H), 3.64 (s, 3H), 3.47-3.29 (m, 2H), 3.25-3.13 (m, 2H), 3.11-2.91 (m, 3H), 2.26-2.12 (m, 2H), 2.12-1.71 (m, 6H). MS (APCI+) m/z 427.1 (M+H)⁺.

Example I-138 7-methoxy-N-(naphthalene-1-sulfonyl)-4-(oxolan-2-yl)-2,3-dihydro-1H-indene-1-carboxamide Example I-138A ethyl 4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylate

A solution of Example I-19B (4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid) (1 g, 3.69 mmol) in ethanol (13 mL) was treated with 9 drops of concentrated H₂SO₄ and heated at 84° C. for 2 hours. The reaction mixture was cooled to room temperature, treated with 2 g of NaHCO₃, and stirred at room temperature for 15 minutes. The mixture was concentrated in vacuo. The residue was treated with ethyl acetate and the resulting mixture was filtered, concentrated, and chromatographed on silica gel, eluting with CH₂Cl₂ to provide the title compound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 7.40 (dd, J=8.6, 0.8 Hz, 1H), 6.84-6.77 (m, 1H), 4.16-4.01 (m, 3H), 3.73 (s, 3H), 3.03-2.93 (m, 1H), 2.87 (ddd, J=16.1, 8.9, 5.9 Hz, 1H), 2.41 (dtd, J=12.9, 9.0, 6.1 Hz, 1H), 2.12 (ddt, J=12.8, 8.9, 5.8 Hz, 1H), 1.24-1.16 (m, 3H). MS (ESI+) m/z 299, 301 (M+H)⁺.

Example I-138B ethyl 7-methoxy-4-(tetrahydrofuran-2-yl)-2,3-dihydro-1H-indene-1-carboxylate

A mixture of Example I-138A (ethyl 4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylate) (25 mg, 0.084 mmol), [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N¹,N¹′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate ([Ir{dF(CF₃)ppy}2(dtbpy)]PF₆) (2.8 mg, 2.5 μM), quinuclidine (0.93 mg, 8.4 μM), and potassium carbonate (23 mg, 0.17 mmol) under nitrogen was treated with a mixture of 4,4′-di-tert-butyl-2,2′-bipyridine (1.1 mg, 4.2 μM) and nickel(II) chloride ethylene glycol dimethyl ether complex (0.93 mg, 4.2 micromol) in tetrahydrofuran (0.5 mL). The resulting mixture was irradiated with 450 nM light (140 Watt) for 15 hours. The mixture was concentrated to dryness and the residue was chromatographed on silica gel eluting with a gradient of 15% to 100% tert-butyl methyl ether in heptanes to provide the title compound. LC/MS (APCI+) m/z 291.5 (M+H)⁺.

Example I-138C 7-methoxy-4-(tetrahydrofuran-2-yl)-2,3-dihydro-1H-indene-1-carboxylic acid

A solution of Example I-138B (ethyl 7-methoxy-4-(tetrahydrofuran-2-yl)-2,3-dihydro-1H-indene-1-carboxylate) (61 mg, 0.210 mmol) in tetrahydrofuran (1.5 mL) was diluted with methanol (1.5 mL), treated with 1 M aqueous NaOH (1 mL), stirred at room temperature for 20 minutes, heated to 60° C. for 2 hours, and cooled. The mixture was partitioned between tert-butyl methyl ether (25 mL) and 1 M aqueous HCl (10 mL). The layers were separated and the aqueous layer was extracted with tert-butyl methyl ether (25 mL). The combined tert-butyl methyl ether layers were washed with brine, dried (MgSO₄), filtered, and concentrated to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.32-7.25 (m, 1H), 6.75 (d, J=8.5 Hz, 0.6H), 6.73 (d, J=8.3 Hz, 0.4H), 4.92-4.82 (m, 1H), 4.14-4.05 (m, 2H), 3.94-3.82 (m, 1H), 3.89 (s, 1.8H), 3.87 (s, 1.2H), 3.14-2.99 (m, 1H), 2.96-2.88 (m, 1H), 2.61-2.49 (m, 1H), 2.43-2.20 (m, 2H), 2.06-1.95 (m, 2H), 1.79-1.65 (m, 1H). LC/MS (APCI+) m/z 263 (M+H)⁺.

Example I-138D 7-methoxy-N-(naphthalene-1-sulfonyl)-4-(oxolan-2-yl)-2,3-dihydro-1H-indene-1-carboxamide

A mixture of Example I-138C (7-methoxy-4-(tetrahydrofuran-2-yl)-2,3-dihydro-1H-indene-1-carboxylic acid) (14.8 mg, 0.056 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.63 mg, 0.113 mmol) and naphthalene-1-sulfonamide (15.20 mg, 0.073 mmol) in N,N-dimethylformamide (0.3 mL) was treated with 4-dimethylaminopyridine (7.58 mg, 0.062 mmol) and stirred overnight. The mixture was partitioned between tert-butyl methyl ether (75 mL) and 1 M aqueous HCl (25 mL). The layers were separated and the aqueous layer was extracted with tert-butyl methyl ether (25 mL). The combined tert-butyl methyl ether layers were washed with 0.1 M aqueous HCl (15 mL), washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was chromatographed on silica gel, eluting with a gradient of 25% to 50% [200:1:1 ethyl acetate:HCOOH:H₂O] in heptanes to provide the title compound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.48 (s, 1H), 8.67 (d, J=8.7 Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.27-8.24 (m, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.81-7.77 (m, 1H), 7.73-7.65 (m, 2H), 7.07 (d, J=8.3 Hz, 1H), 6.56-6.53 (m, 1H), 4.69-4.63 (m, 1H), 3.92 (ddd, J=6.3, 8.5, 14.9 Hz, 2H), 3.71 (qd, J=3.0, 7.3 Hz, 1H), 3.12 (s, 1.6H), 3.09 (s, 1.3H), 2.74 (td, J=7.2, 15.2, 16.0 Hz, 2H), 2.27-2.18 (m, 1H), 2.18-2.08 (m, 1H), 1.93-1.84 (m, 2H), 1.83-1.73 (m, 1H), 1.55-1.46 (m, 1H). LC/MS (APCI+) m/z 452 (M+H)⁺.

Example I-139 7-methoxy-4-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-139A 4-(hydroxymethyl)-7-methoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of methyl 7-methoxy-1-((naphthalen-1-ylsulfonyl)carbamoyl)-2,3-dihydro-1H-indene-4-carboxylate (217 mg, 0.494 mmol) from Example I-124A in dichloromethane (7 mL) at 0° C. was added a 1 M solution of diisobutylaluminum hydride in dichloromethane (1 mL, 1.000 mmol). The reaction was stirred for 30 minutes and warmed to room temperature over 3 hours. The reaction was cooled in an ice bath and was quenched with 10 mL 1 N aqueous citric acid. The solvent was evaporated in vacuo and the resulting residue was chromatographed using a 12 g silica gel cartridge with 0-100% ethyl acetate/heptanes over a period of 6 minutes to provide the title compound. ¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ ppm 12.50 (s, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.30 (d, J=8.2 Hz, 1H), 8.27 (d, J=7.5 Hz, 1H), 8.15 (d, J=8.2 Hz, 1H), 7.83-7.78 (m, 1H), 7.75-7.65 (m, 2H), 7.07 (d, J=8.2 Hz, 1H), 6.55 (d, J=8.3 Hz, 1H), 4.86 (s, 1H), 4.41-4.17 (m, 2H), 3.95 (dd, J=9.1, 5.8 Hz, 1H), 3.10 (d, J=1.1 Hz, 3H), 2.73 (q, J=6.6 Hz, 2H), 2.23 (dq, J=14.9, 8.0 Hz, 1H), 1.79 (dq, J=14.0, 6.8 Hz, 1H). MS (APCI+) m/z 394 (M+H)⁺.

Example I-139B 7-methoxy-4-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of 4-(hydroxymethyl)-7-methoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide (40 mg, 0.097 mmol) from Example I-139A in N,N-dimethylformamide (0.8 mL) at 0° C. was added sodium hydride (7.78 mg, 0.194 mmol), as a 60% dispersion in mineral oil. After 15 minutes, iodomethane (0.012 mL, 0.194 mmol) was added and the reaction was stirred at 0° C. for 2 hours. The mixture was quenched via addition of 1 N aqueous citric acid (1 mL) and was extracted with ethyl acetate. The crude material was purified with a 12 g silica gel cartridge using a gradient of 0-100% ethyl acetate/heptanes over 15 minutes to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.52 (s, 1H), 8.73-8.66 (m, 1H), 8.31-8.21 (m, 2H), 8.12 (d, J=8.0 Hz, 1H), 7.83-7.75 (m, 1H), 7.74-7.62 (m, 2H), 7.03 (d, J=8.2 Hz, 1H), 6.55 (d, J=8.2 Hz, 1H), 4.22 (s, 2H), 3.93 (dd, J=9.1, 5.6 Hz, 1H), 3.18 (s, 3H), 3.12 (s, 3H), 2.73 (m, 2H), 2.31-2.15 (m, 1H), 1.87-1.69 (m, 1H). MS (ESI+) m/z 426 (M+H)⁺.

Example I-140 7-methoxy-4-(2-methylpropyl)-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A suspension of Example I-44 (4-bromo-7-methoxy-N-(quinolin-5-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide) (35.4 mg, 0.077 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (5.61 mg, 7.67 μmol) in tetrahydrofuran (0.5 mL) was treated with 1 M tert-butylzinc bromide in tetrahydrofuran (460 μl, 0.230 mmol). The mixture was stirred over the weekend at room temperature, heated to 60° C. for 2.5 hours and then heated to 80° C. for 2.5 hours. The mixture was cooled and partitioned between tert-butyl methyl ether (30 mL) and 1 M aqueous HCl (10 mL). The tert-butyl methyl ether layer was washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was chromatographed on silica gel, eluting with a gradient of 25% to 100% [200:1:1 ethyl acetate:HCOOH:H₂O] in heptanes to provide the title compound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.59 (s, 1H), 9.09 (dd, J=1.6, 4.2 Hz, 1H), 9.07-9.04 (m, 1H), 8.38-8.35 (m, 1H), 8.34 (dd, J=1.3, 7.5 Hz, 1H), 7.94 (dd, J=7.5, 8.4 Hz, 1H), 7.83 (dd, J=4.2, 8.8 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.51 (d, J=8.3 Hz, 1H), 3.93 (dd, J=5.9, 8.9 Hz, 1H), 3.07 (s, 3H), 2.80-2.65 (m, 2H), 2.30-2.19 (m, 3H), 1.84-1.74 (m, 1H), 1.73-1.65 (m, 1H), 0.81 (d, J=3.7 Hz, 3H), 0.79 (d, J=3.7 Hz, 3H). LC/MS (APCI+) m/z 439 (M+H)⁺.

Example I-141 (1S)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was added 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (Example I-127C, 79 mg, 0.323 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (124 mg, 0.646 mmol), and N,N-dimethylpyridin-4-amine (43.4 mg, 0.355 mmol) in dichloromethane. 1-Methyl-1H-indazole-7-sulfonamide (Example I-97A, 75 mg, 0.355 mmol) was added. The reaction was stirred overnight at room temperature. The solvent was removed under a stream of nitrogen and the residue was reconstituted in methanol and was purified using preparative reverse phase HPLC/MS method TFA8 to provide the racemate of the title compound. The racemate was separated by chiral preparative SFC chromatography using a WHELK-O (S,S), column size 21×250 mm, serial number 43170, 5 micron, using a concentration of 25 mg/mL in 3:1 methanol/dichloromethane at a flow rate of 49 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound as the first eluting isomer. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.31 (s, 1H), 8.14 (d, J=8.2 Hz, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 4.42 (s, 3H), 4.00-3.92 (m, 1H), 3.46-3.34 (m, 1H), 3.22 (s, 3H), 2.84-2.69 (m, 2H), 2.34-2.29 (m, 1H), 2.24-2.17 (m, 2H), 2.00-1.88 (m, 4H), 1.78-1.71 (m, 1H). MS (APCI+) m/z 440.1 (M+H)⁺.

Example I-142 (1R)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-142 was isolated as the second eluting isomer from the preparative SFC separation described in Example I-141. ¹H NMR (500 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.32 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.07 (d, J=7.5 Hz, 1H), 7.31 (t, J=7.7 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 4.43 (s, 3H), 3.98 (d, J=7.8 Hz, 1H), 3.40 (q, J=8.7 Hz, 1H), 3.22 (s, 3H), 2.85 2.67 (m, 2H), 2.39-2.27 (m, 1H), 2.26-2.17 (m, 2H), 2.03-1.87 (m, 4H), 1.79-1.72 (m, 1H). MS (APCI+) m/z 440.1 (M+H)⁺.

Example I-143 (7S)-2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

Example I-132 (164.4 mg) was separated by chiral preparative SFC chromatography using a WHELK-O (S,S), column size 21×250 mm, serial number 43170, 5 micron, using a concentration of 15 mg/mL in methanol at a flow rate of 56 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound as the first eluting isomer. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.32 (s, 1H), 8.17 (dd, J=8.0, 1.1 Hz, 1H), 8.10 (dd, J=7.6, 1.1 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.59 (d, J=8.6 Hz, 1H), 4.43 (s, 3H), 4.36 (dd, J=5.6, 2.4 Hz, 1H), 3.48 (s, 3H), 3.43-3.25 (m, 2H), 3.01 (dd, J=13.7, 2.5 Hz, 1H), 2.23-2.10 (m, 2H), 2.07-1.82 (m, 3H), 1.82-1.69 (m, 1H). MS (APCI+) m/z 426.1 (M+H)⁺.

Example I-144 (7R)-2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

Example I-144 was isolated as the second enantiomer from the preparative SFC separation described in Example I-143. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.31 (s, 1H), 8.15 (dd, J=8.0, 1.1 Hz, 1H), 8.08 (dd, J=7.5, 1.1 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.58 (d, J=8.6 Hz, 1H), 4.42 (s, 3H), 4.34 (dd, J=5.6, 2.4 Hz, 1H), 3.48 (s, 3H), 3.42-3.25 (m, 2H), 3.01 (dd, J=13.7, 2.5 Hz, 1H), 2.23-2.10 (m, 2H), 2.08-1.84 (m, 3H), 1.82-1.69 (m, 1H). MS (APCI+) m/z 426.1 (M+H)⁺.

Example I-145 (7S)-2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

Example I-137 (46 mg) was separated by chiral preparative SFC chromatography using a WHELK-O (S,S), column size 21×250 mm, serial number 43170, 5 micron, using a concentration of 15 mg/mL in methanol at a flow rate of 45 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound as the first eluting isomer. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 7.09 (dd, J=7.8, 1.3 Hz, 1H), 7.05-6.99 (m, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.72 (dd, J=8.0, 1.3 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 4.36 (dd, J=5.6, 2.5 Hz, 1H), 3.64 (s, 3H), 3.45-3.30 (m, 2H), 3.24-3.12 (m, 2H), 3.08-2.93 (m, 3H), 2.24-2.14 (m, 2H), 2.09-1.97 (m, 2H), 1.97-1.86 (m, 1H), 1.86-1.72 (m, 3H). MS (APCI+) m/z 427.1 (M+H)⁺.

Example I-146 (7R)-2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

Example I-146 was isolated as the second enantiomer from the preparative SFC separation described in Example I-145. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 7.09 (dd, J=7.8, 1.4 Hz, 1H), 7.07-6.99 (m, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.72 (dd, J=8.0, 1.4 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 4.36 (dd, J=5.6, 2.4 Hz, 1H), 3.64 (s, 3H), 3.46-3.29 (m, 2H), 3.18 (td, J=9.0, 7.8, 4.4 Hz, 2H), 3.01 (ddt, J=9.5, 6.5, 2.8 Hz, 3H), 2.25-2.12 (m, 2H), 2.10-1.87 (m, 3H), 1.87-1.71 (m, 3H). MS (APCI+) m/z 427.1 (M+H)⁺.

Example I-147 (7S)-2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

A solution of Example I-102H (2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid) (234 mg, 1.007 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (386 mg, 2.015 mmol) and quinoline-5-sulfonamide (231 mg, 1.108 mmol) in N,N-dimethylformamide (4 mL) was treated with 4-dimethylaminopyridine (135 mg, 1.108 mmol). The mixture was stirred overnight and was partitioned between tert-butyl methyl ether (100 mL) and 0.5 M aqueous HCl (25 mL). The tert-butyl methyl ether layer was washed with 0.2 M aqueous HCl (15 mL), washed with brine, dried (MgSO₄), filtered, and concentrated. The residue was chromatographed on silica gel, eluting with a gradient of 25% to 50% [200:1:1 ethyl acetate:HCOOH:H₂O] in heptanes to provide the racemate of the title compound. The enantiomers of this racemate were separated by Supercritical Fluid Chromatography (SFC) using a 21×250 mm ChiralPak AD-H chiral column eluting with 20% methanol in liquid CO₂ using a flow rate of 80 mL/minute to provide the title compound as the first peak to elute from the column. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.83 (s, 1H), 9.08 (dd, J=1.7, 4.2 Hz, 1H), 9.02 (d, J=8.5 Hz, 1H), 8.39-8.35 (m, 2H), 7.94 (t, J=8.0 Hz, 1H), 7.81 (dd, J=4.2, 8.7 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.53 (d, J=8.6 Hz, 1H), 4.33 (dd, J=2.5, 5.7 Hz, 1H), 3.39-3.23 (m, 5H), 2.84 (dd, J=2.5, 13.8 Hz, 1H), 2.11 (ddt, J=3.4, 6.3, 8.8 Hz, 2H), 2.00-1.82 (m, 3H), 1.76-1.68 (m, 1H). LC/MS (APCI+) m/z 423 (M+H)⁺.

Example I-148 (7R)-2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

The enantiomers of the racemate from Example I-147 were separated by Supercritical Fluid Chromatography (SFC) using a 21×250 mm ChiralPak AD-H chiral column eluting with 20% methanol in liquid CO₂ using a flow rate of 80 mL/minute to provide the title compound as the second peak to elute from the column. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.83 (s, 1H), 9.08 (dd, J=1.7, 4.2 Hz, 1H), 9.02 (d, J=8.5 Hz, 1H), 8.39-8.35 (m, 2H), 7.94 (t, J=8.0 Hz, 1H), 7.81 (dd, J=4.2, 8.7 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.53 (d, J=8.6 Hz, 1H), 4.33 (dd, J=2.5, 5.7 Hz, 1H), 3.39-3.23 (m, 5H), 2.84 (dd, J=2.5, 13.8 Hz, 1H), 2.11 (ddt, J=3.4, 6.3, 8.8 Hz, 2H), 2.00-1.82 (m, 3H), 1.76-1.68 (m, 1H). LC/MS (APCI+) m/z 423 (M+H)⁺.

Example I-149 7-methoxy-3,3-dimethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example I-149A 1-(2-methoxyphenyl)-3-methylbut-2-en-1-one

N-methoxy-N,3-dimethylbut-2-enamide (2.500 g, 17.46 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to −40° C. using a dry ice/acetone bath. A 1 M solution of (2-methoxyphenyl)magnesium bromide (20.95 mL, 20.95 mmol) in tetrahydrofuran was added dropwise over about 10 minutes. The reaction was allowed to warm to room temperature overnight. The reaction was diluted with 200 mL of methyl tert-butyl ether, washed with saturated aqueous ammonium chloride (50 mL) and brine (50 mL) then dried over sodium sulfate, filtered, and concentrated. The crude material was chromatographed using an 80 g silica gel cartridge with a gradient of 5-100% ethyl acetate/hexanes over 40 minutes to provide the title compound. ¹H NMR (501 MHz, Chloroform-d) δ ppm 7.57 (dd, J=7.6, 1.8 Hz, 1H), 7.43 (ddd, J=8.2, 7.3, 1.8 Hz, 1H), 7.02 (td, J=7.5, 1.0 Hz, 1H), 6.97 (dd, J=8.4, 0.9 Hz, 1H), 6.64 (hept, J=1.2 Hz, 1H), 3.90 (s, 3H), 2.25 (d, J=1.3 Hz, 3H), 1.99 (d, J=1.3 Hz, 3H). MS (APCI+) m/z 191 (M+H⁺).

Example I-149B 7-methoxy-3,3-dimethyl-2,3-dihydro-1H-inden-1-one

A 30 mL vial, open to air via a vent needle, was charged with aluminum chloride (4.00 g, 30.0 mmol) and sodium chloride (0.800 g, 13.69 mmol) and heated at 200° C. The melt was removed from the heat and neat 1-(2-methoxyphenyl)-3-methylbut-2-en-1-one (0.800 g, 4.21 mmol) from Example I-149A was added dropwise while stirring. The reaction was returned to the heating block for 1 minute. The reaction was cooled, quenched with ice, and extracted with ethyl acetate (4×50 mL). The crude extracts were dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was taken up in acetone (14 mL) and treated with potassium carbonate (0.872 g, 6.31 mmol) and dimethyl sulfate (0.597 mL, 6.31 mmol). The mixture was stirred at ambient temperature overnight. The reaction was quenched with triethylamine (0.5 mL), filtered, and the solvent was removed in vacuo. The crude material was chromatographed using a 40 g silica gel cartridge with a gradient of 0-50% ethyl acetate/heptane over 20 minutes to provide the title compound. ¹H NMR (501 MHz, Chloroform-d) δ ppm 7.58 (dd, J=8.2, 7.6 Hz, 1H), 7.07 (dd, J=7.7, 0.7 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 3.98 (s, 3H), 2.60 (s, 2H), 1.42 (s, 6H). MS (APCI+) m/z 191 (M+H)⁺.

Example I-149C 7-methoxy-3,3-dimethyl-2,3-dihydro-1H-indene-1-carbonitrile

To a solution of 7-methoxy-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (0.205 g, 1.078 mmol) from Example I-149B and zinc(II) iodide (0.014 g, 0.043 mmol) in dichloromethane (3 mL) cooled to 0° C. was added slowly trimethylsilanecarbonitrile (0.404 mL, 3.23 mmol). The mixture was allowed to warm to room temperature over an hour. The solvent was removed in vacuo and the residue was dissolved in acetic acid (3 mL) and concentrated aqueous HCl (0.3 mL). Tin(II) chloride (0.895 g, 4.72 mmol) was added. The mixture was heated at 90° C. for 2 hours. The reaction was cooled down to ambient temperature, filtered and washed with dichloromethane. The solvent was removed under a stream of nitrogen. The residue was dissolved in dichloromethane and purified via chromatography on 10 g silica gel cartridge, eluting with ethyl acetate/methanol (9:1) in heptane at 0-80% gradient to provide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 7.27-7.12 (m, 2H), 6.77-6.68 (m, 2H), 3.82 (dd, J=8.8, 6.1 Hz, 1H), 3.70 (s, 3H), 2.08 (dd, J=12.6, 8.8 Hz, 1H), 1.98 (dd, J=12.6, 6.1 Hz, 1H), 1.89 (s, 1H), 1.25 (s, 3H), 1.13 (s, 3H). MS (APCI+) m/z 220 (M+H⁺).

Example I-149D 7-methoxy-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxylic acid

A solution of 7-methoxy-3,3-dimethyl-2,3-dihydro-1H-indene-1-carbonitrile (71 mg, 0.353 mmol) from Example I-149C and sodium hydroxide (137 mg, 3.43 mmol) in water (1 mL) and ethanol (1 mL) was warmed at 100° C. for 72 hours. The solvent was removed and the crude material was acidified with 1.5 mL of 3 N aqueous HCl. The precipitate was triturated, and the mixture was filtered and washed with 1×2 mL water to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.05 (s, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.75 (dd, J=7.8, 6.1 Hz, 2H), 3.82 (dd, J=9.1, 6.3 Hz, 1H), 3.69 (s, 3H), 2.22 (dd, J=12.7, 9.1 Hz, 1H), 1.95 (dd, J=12.7, 6.3 Hz, 1H), 1.23 (s, 3H), 1.13 (s, 3H). MS (APCI+) m/z 221 (M+H⁺).

Example I-149E 7-methoxy-3,3-dimethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A mixture of 7-methoxy-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxylic acid (70 mg, 0.318 mmol) from Example I-149D, N,N-dimethylpyridin-4-amine (51 mg, 0.417 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (160 mg, 0.835 mmol) in DMA (dimethylacetamide, 1 mL) was stirred at room temperature for 20 minutes. To the mixture was added naphthalene-1-sulfonamide (65.9 mg, 0.318 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with 1.0 mL of 1 N aqueous HCl. The reaction was diluted with dichloromethane and put through an aqueous/organic extractor tube. The volatiles were removed in vacuo and the resulting solution was diluted with methanol and purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 10.02 (s, 1H), 8.50 (dd, J=7.4, 1.2 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.55-7.42 (m, 2H), 7.29 (t, J=7.9 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 3.99 (s, 3H), 3.90 (dd, J=9.2, 2.4 Hz, 1H), 2.41 (dd, J=13.2, 2.3 Hz, 1H), 1.90 (dd, J=13.2, 9.2 Hz, 1H), 1.18 (s, 3H), 0.82 (s, 3H). MS (APCI+) m/z 410 (M+H⁺).

Example I-151 (1R)-4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Into a 4 mL vial was added 4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (56.8 mg, 0.230 mmol), N¹-(ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (88 mg, 0.461 mmol), and N,N-dimethylpyridin-4-amine (31.0 mg, 0.254 mmol) in dichloromethane (1 mL). Pyrazolo[1,5-a]pyridine-4-sulfonamide (Example I-135B, 50 mg, 0.254 mmol) was added. The reaction was stirred for 2 hours at room temperature. The solvent was removed under a stream of nitrogen and the residue was reconstituted in methanol and purified using preparative reverse phase HPLC/MS method TFA7 to provide the racemate of title compound. The racemate was separated by chiral preparative SFC chromatography using a WHELK-O (S,S), column size 21×250 mm, serial number 43170, 5 micron, using a concentration of 14.25 mg/mL in methanol at a flow rate of 80 g/minutes at isocratic 30% methanol in CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.99 (dt, J=7.2, 1.0 Hz, 1H), 8.27 (d, J=2.3 Hz, 1H), 7.89 (dd, J=7.2, 1.0 Hz, 1H), 7.10 (t, J=7.1 Hz, 1H), 7.06-6.98 (m, 2H), 6.61 (d, J=8.4 Hz, 1H), 3.93 (dd, J=9.1, 5.7 Hz, 1H), 3.39 (p, J=9.0, 8.5 Hz, 1H), 3.22 (s, 3H), 2.80-2.62 (m, 2H), 2.32 2.11 (m, 3H), 2.04-1.68 (m, 5H). MS (APCI+) m/z 426.1 (M+H)⁺.

Example I-152 7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A mixture of 7-methoxy-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxylic acid from Example I-149D (118 mg, 0.536 mmol), N,N-dimethylpyridin-4-amine (82 mg, 0.671 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (209 mg, 1.090 mmol) in dichloromethane (2 mL) was stirred at room temperature for 20 minutes. To the mixture was added quinoline-5-sulfonamide (112 mg, 0.536 mmol). The reaction was stirred at room temperature overnight. The crude reaction was acidified with 1.0 mL of 1 N aqueous HCl. The reaction was diluted with water and dichloromethane and put through an aqueous/organic extractor tube. The volatiles were removed in vacuo and the resulting solution was diluted with methanol and was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to provide crude title compound. The material was triturated with methanol to provide the title compound. ¹H NMR (400 MHz, Chloroform-d) δ ppm 10.11 (s, 1H), 8.97 (dd, J=4.3, 1.6 Hz, 1H), 8.85 (ddd, J=8.8, 1.7, 0.9 Hz, 1H), 8.54 (dd, J=7.5, 1.2 Hz, 1H), 8.39 (dt, J=8.5, 1.1 Hz, 1H), 7.85 (dd, J=8.5, 7.4 Hz, 1H), 7.41 (dd, J=8.7, 4.3 Hz, 1H), 7.35-7.29 (m, 1H), 6.84 (dd, J=8.2, 0.8 Hz, 1H), 6.76 (dd, J=7.6, 0.8 Hz, 1H), 4.02 (s, 3H), 3.93 (dd, J=9.2, 2.3 Hz, 1H), 2.43 (dd, J=13.2, 2.3 Hz, 1H), 1.92 (dd, J=13.2, 9.2 Hz, 1H), 1.20 (s, 3H), 0.81 (s, 3H). MS (APCI+) m/z 411 (M+H⁺).

Example I-153 (1S)-7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

7-Methoxy-3,3-dimethyl-N-(quinolin-5-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide from Example I-152 (98 mg) was separated by chiral preparative SFC chromatography using a ChiralCel® AD-H column size 21×250 mm, 5 micron, serial Number: ADHOSAQB001-210041, using a concentration 24.5 mg in methanol at a flow rate of 59 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (500 MHz, Chloroform-d) δ ppm 10.13 (s, 1H), 8.96 (dd, J=4.4, 1.6 Hz, 1H), 8.79 (ddd, J=8.7, 1.5, 0.8 Hz, 1H), 8.54 (dd, J=7.4, 1.2 Hz, 1H), 8.37 (dt, J=8.4, 1.1 Hz, 1H), 7.84 (dd, J=8.5, 7.4 Hz, 1H), 7.39 (dd, J=8.8, 4.2 Hz, 1H), 7.35-7.30 (m, 1H), 6.84 (dd, J=8.1, 0.8 Hz, 1H), 6.77 (dd, J=7.6, 0.8 Hz, 1H), 4.02 (s, 3H), 3.94 (dd, J=9.2, 2.3 Hz, 1H), 2.44 (dd, J=13.2, 2.4 Hz, 1H), 1.93 (dd, J=13.2, 9.2 Hz, 1H), 1.20 (s, 3H), 0.82 (s, 3H). MS (APCI+) m/z 411 (M+H⁺). R_(T) (chiral SFC)=3.4 minutes.

Example I-154 (1R)-7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

7-Methoxy-3,3-dimethyl-N-(quinolin-5-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide from Example I-152 (98 mg) was separated by chiral preparative SFC chromatography using a ChiralCel® AD-H column size 21×250 mm, 5 micron, serial Number: ADHOSAQB001-210041, using a concentration 24.5 mg in methanol at a flow rate of 59 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (500 MHz, Chloroform-d) δ μm 10.10 (s, 1H), 8.95 (dd, J=4.2, 1.6 Hz, 1H), 8.77 (ddd, J=8.7, 1.6, 0.9 Hz, 1H), 8.54 (dd, J=7.4, 1.2 Hz, 1H), 8.36 (dt, J=8.5, 1.1 Hz, 1H), 7.83 (dd, J=8.5, 7.4 Hz, 1H), 7.38 (dd, J=8.8, 4.2 Hz, 1H), 7.32 (ddd, J=8.2, 7.5, 0.6 Hz, 1H), 6.85 (dd, J=8.2, 0.8 Hz, 1H), 6.77 (dd, J=7.6, 0.7 Hz, 1H), 4.03 (s, 3H), 3.94 (dd, J=9.2, 2.2 Hz, 1H), 2.44 (dd, J=13.2, 2.3 Hz, 1H), 1.93 (dd, J=13.2, 9.3 Hz, 1H), 1.21 (s, 3H), 0.82 (s, 3H). MS (APCI+) m/z 411 (M+H⁺). R_(T) (chiral SFC)=4.2 minutes.

Example I-155 (7R)-2-cyclobutyl-5-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

The racemate of the title compound was prepared and isolated using the same procedure as described in Example I-132, substituting Example I-100A for 1-methyl-1H-indazole-7-sulfonamide. The material was separated by chiral preparative SFC chromatography using a ChiralPak AD-H, column size 21×250 mm, serial number ADHOSAQB001-210041, 5 micron, using a concentration of 20 mg/mL in methanol at a flow rate of 49 g/minute CO₂ and UV monitoring at 220 nm to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.03 (dd, J=7.3, 1.3 Hz, 1H), 7.99 7.91 (m, 2H), 7.84 (dd, J=8.9, 7.3 Hz, 1H), 6.89 (d, J=8.6 Hz, 1H), 6.54 (d, J=8.5 Hz, 1H), 4.06 (dd, J=5.7, 2.5 Hz, 1H), 3.56 (s, 3H), 3.41-3.25 (m, 2H), 2.98 (dd, J=13.6, 2.5 Hz, 1H), 2.89 (s, 3H), 2.25-2.12 (m, 2H), 2.11-1.86 (m, 3H), 1.83-1.72 (m, 1H). MS (APCI+) m/z 426.1 (M+H)⁺.

Example 11-3 4-chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

4-Chloroindane-1-carboxylic acid (CAS#66041-25-6, 50 mg, 0.26 mmol) and 1,1′-carbonyldiimidazole (CAS#530-62-1, 68 mg, 0.42 mmol) were combined in anhydrous tetrahydrofuran (1 mL), heated at 50° C. and stirred for 30 minutes. The mixture was cooled to room temperature, 2-methylbenzenesulfonamide (CAS#88-19-7, 46 mg, 0.27 mmol) and DBU (2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine, CAS#6674-22-2, 42 μL, 0.29 mmol) were added, and the resultant mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the resultant residue was taken up in acetonitrile and filtered. The crude material was purified by reverse-phase HPLC (method 1) to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.59 (s, 1H), 7.95-7.92 (m, 1H), 7.59-7.54 (m, 1H), 7.43-7.39 (m, 2H), 7.29-7.23 (m, 1H), 7.23-7.20 (m, 2H), 4.13 (dd, J=5.5, 8.5 Hz, 1H), 2.97-2.80 (m, 2H), 2.63 (s, 3H), 2.32-2.08 (m, 2H). MS (ESI+) m/z 350 (M+H)⁺.

Example 11-29 (1S)-4-chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

4-Chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide (Example II-3, 52 mg 0.15 mmol) was dissolved in methanol (1.5 mL). The isomers were separated by chiral SFC (injected 250 μL (8.7 mg per injection), and eluted isocratically with methanol (0.1% diethylamine), 15% and 85% carbon dioxide, at 100 mL per minute (120 bar, 40° C.) over YMC amylose-C stationary phase). The faster eluting isomer eluted at 3.4 minutes and the slower eluting isomer, the title compound, eluted at 4.4 minutes. The process was repeated seven times to complete the purification. The fractions that contained the title compound were combined, concentrated and assessed for enantiomeric excess. The title compound was isolated as the diethylamine salt, ee=96.2%, 100%. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.15 (1H, s), 7.78-7.75 (1H, m), 7.29-7.22 (2H, m), 7.19-7.09 (4H, m), 3.80-3.72 (1H, m), 2.96-2.89 (5H, m), 2.34-2.20 (1H, m), 2.12-2.02 (1H, m), 1.16 (dd, J=7.3, 7.3 Hz, 6H). MS (ESI+) m/z 350 (M+H)⁺.

Example II-36 N-(2-methylbenzene-1-sulfonyl)-4-phenyl-2,3-dihydro-1H-indene-1-carboxamide Example II-36A 4-bromoindane-1-carbonitrile

To a stirred suspension of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (CAS#36635-61-7, 7.56 g, 38.7 mmol) in dry 1,2-dimethoxyethane (115 mL) cooled to 0° C. under a stream of nitrogen with an ice bath was added potassium tert-butoxide (CAS#865-47-4, 7.56 g, 70.0 mmol) in small portions over 15 minutes. tert-Butanol (45 mL) was added. The stirring was continued with cooling for another 15 minutes and 4-bromoindan-1-one was added (CAS#15115-60-3, 7.28 g, 34.7 mmol). After 20 minutes, the ice bath was removed. After 6 hours, water was added, and the mixture was extracted with ethyl acetate (three times). The combined organic layers were dried (MgSO₄), filtered, concentrated under reduced pressure onto silica, and purified by flash chromatography using Biotage® SNAP 100 g silica column, eluting with 0-100% ethyl acetate in iso-hexane to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.45 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.15 (dd, J=7.7, 7.7 Hz, 1H), 4.21 (t, J=8.4 Hz, 1H), 3.14 (ddd, J=4.1, 8.9, 16.6 Hz, 1H), 3.02-2.92 (m, 1H), 2.65-2.56 (m, 1H), 2.40 (ddd, J=8.3, 13.0, 17.0 Hz, 1H).

Example II-36B 4-bromoindane-1-carboxamide

To a stirred solution of 4-bromoindane-1-carbonitrile (4.7 g, 21.2 mmol) in methanol (50 mL) was added water (50 mL) and concentrated aqueous sodium hydroxide (50 mL). The resultant suspension was stirred and heated to 80° C. for 24 hours. The reaction mixture was concentrated under reduced pressure and extracted with dichloromethane (twice). The combined organic phases were concentrated under reduced pressure to provide the crude title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 7.38 (d, J=7.5 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.06 (dd, J=7.7, 7.7 Hz, 1H), 3.89-3.83 (m, 1H), 2.98-2.71 (m, 2H), 2.35-2.06 (m, 2H).

Example II-36C 4-bromoindane-1-carboxylic acid

Concentrated sulfuric acid (70 mL) was diluted with water (30 mL) and at room temperature sodium nitrite (CAS#7632-00-0, 2.2 g, 32 mmol) was added followed by 4-bromoindane-1-carboxamide (5.1 g, 21.2 mmol). After 3 hours, the mixture was diluted with water and extracted with ethyl acetate (three times). The combined organic layers were dried (MgSO₄), filtered and concentrated under reduced pressure to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 7.43 (d, J=7.9 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.15 (dd, J=7.7, 7.7 Hz, 1H), 4.12 (dd, J=7.5, 7.5 Hz, 1H), 3.02-2.81 (m, 2H), 2.29 (q, J=7.5 Hz, 2H).

Example II-36D 4-phenylindane-1-carboxylic acid

A mixture of phenylboronic acid (CAS#98-80-6, 62 mg 0.51 mmol) and 4-bromoindane-1-carboxylic acid (100 mg, 0.41 mmol) in 1,2-dimethoxyethane (3 mL) and an aqueous solution of 1 M sodium bicarbonate solution (1 mL) was deoxygenated under N₂ flow for 5 minutes. Palladium(II)bis(triphenylphosphine) dichloride (CAS#13965-03-2, 20 mg, 0.028 mmol) was added and deoxygenation was continued for another 2 minutes. The reaction vessel was sealed and was stirred at 100° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, partitioned between ethyl acetate and water, acidified to pH 2 with dilute aqueous HCl, and extracted with ethyl acetate (three times). The combined organic layers were dried (MgSO₄), filtered and concentrated under reduced pressure to provide the crude title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.26-8.23 (m, 1H), 7.70-7.24 (m, 7H), 4.17-4.09 (m, 1H), 3.22-3.13 (m, 1H), 3.01-2.91 (m, 1H), 2.48-2.28 (m, 2H).

Example II-36E N-(2-methylbenzene-1-sulfonyl)-4-phenyl-2,3-dihydro-1H-indene-1-carboxamide

A solution of 4-phenylindane-1-carboxylic acid (110 mg, 0.46 mmol), DMAP (4-dimethylaminopyridine) (CAS#1122-58-3, 57 mg, 0.46 mmol) and 2-methylbenzenesulfonamide (CAS#88-19-7, 79 mg, 0.46 mmol) was prepared in dichloromethane (1 mL). N-Ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride/EDC (CAS#25952-53-8, 88 mg, 0.46 mmol) was added. The reaction was stirred at room temperature for 18 hours, poured over a 10 g SCX cartridge and eluted with dichloromethane and dichloromethane with 10% methanol (v/v). Fractions containing the title compound were combined and concentrated. The crude material was purified by reversed-phase HPLC (method 2) to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.31-8.27 (m, 1H), 8.18 (dd, J=1.2, 8.0 Hz, 1H), 7.55-7.50 (m, 1H), 7.43-7.29 (m, 9H), 7.18 (dd, J=4.3, 4.3 Hz, 1H), 4.02 (dd, J=6.2, 8.6 Hz, 1H), 3.13-3.04 (m, 1H), 2.99-2.90 (m, 1H), 2.59 (s, 3H), 2.45-2.35 (m, 1H), 2.29-2.19 (m, 1H). MS (ESI+) m/z 392 (M+H)⁺.

Example II-47 4-chloro-N-(naphthalene-1-sulfonyl)-1-[(pyrrolidin-1-yl)methyl]-2,3-dihydro-1H-indene-1-carboxamide

A solution of pyrrolidine (19 μL, 0.23 mmol), 37% formalin (34 μL, 0.46 mmol) and acetic acid (30 μL) in methanol (300 μL) was added to crude Example I-8 (58 mg, <0.15 mmol) with a methanol (150 μL) rinse. After Example I-8 dissolved, the reaction mixture was heated at 60° C. for 11 hours, additional 37% formalin (34 μL, 0.46 mmol) was added and heating at 60° C. was continued another 20 hours before the reaction mixture was brought to room temperature, concentrated and chromatographed on silica (0 to 15% methanol/ethyl acetate) to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.60 (d, J=8.4 Hz, 1H), 8.03 (dd, J=7.3, 1.3 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.93-7.90 (m, 1H), 7.53-7.42 (m, 3H), 7.22 (dd, J=6.2, 2.7 Hz, 1H), 7.08-7.03 (m, 2H), 3.77 (d, J=12.9 Hz, 1H), 3.19 (d, J=12.9 Hz, 1H), 3.13-2.85 (m, 6H), 2.65 (ddd, J=13.2, 8.5, 5.0 Hz, 1H), 2.01 (ddd, J=12.8, 8.5, 6.7 Hz, 1H), 1.78-1.64 (m, 4H). MS (ESI+) m/z 469 (M+H)⁺.

Example II-80 4-chloro-N-(3,4-dihydroquinoline-1(2H)-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide

To a solution of Example I-17A (27 mg, 0.12 mmol), EDAC (1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 46 mg, 0.24 mmol) and DMAP (4-dimethylaminopyridine) (16 mg, 0.13 mmol) in anhydrous dichloromethane (300 μL) was added 3,4-dihydroquinoline-1(2H)-sulfonamide (30 mg, 0.14 mmol). The solution was stirred overnight at room temperature and was placed directly onto silica with a drop of acetic acid in CHCl₃ for chromatography (100% CHCl₃) to provide the title compound. ¹H NMR (501 MHz, CD₂Cl₂) δ ppm 7.71 (bs, 1H), 7.43-7.40 (m, 1H), 7.25 (dd, J=8.0, 0.9 Hz, 1H), 7.16-7.13 (m, 1H), 7.12-7.03 (m, 3H), 6.78-6.75 (m, 1H), 4.02-3.92 (m, 2H), 2.85 (ddd, J=16.9, 8.8, 5.6 Hz, 1H), 2.75-2.68 (m, 3H), 2.24 (ddd, J=13.3, 8.7, 5.5 Hz, 1H), 2.05-1.95 (m, 3H), 1.80 (dq, J=13.9, 7.4 Hz, 1H), 1.73 (dq, J=13.9, 7.4 Hz, 1H), 0.65 (t, J=7.4 Hz, 3H). MS (ESI+) m/z=419 (M+H)⁺.

Example II-81 4-chloro-1-(hydroxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

A solution of the Example I-8 (58 mg, 0.15 mmol) in anhydrous DMI (1,3-dimethyl-2-imidazolidinone) (50 μL) and anhydrous tetrahydrofuran (250 μL) was added slowly dropwise to 1 M LiHMDS (lithium hexamethyldisilazide) in tetrahydrofuran (330 μL) under nitrogen. The mixture was cooled to 0° C. After stirring cold for 20 minutes, it was removed from the bath, and added dropwise to paraformaldehyde (14 mg, ˜0.47 mmol) under nitrogen that had been cooled with a −20° C. bath, followed by a tetrahydrofuran (100 μL) rinse. The resulting suspension was stirred below −15° C. for 20 minutes, removed from the bath, and stirred at room temperature two weeks. The reaction mixture was applied directly to silica for chromatography (40 to 100% methyl tert-butyl ether/heptane then 5 to 20% CH₃CN/methyl tert-butyl ether) to give the impure product, which was repurified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 80% gradient of acetonitrile in 0.1% aqueous TFA] to give the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.08 (bs, 1H), 8.59-8.55 (m, 1H), 8.30-8.26 (m, 2H), 8.11-8.08 (m, 1H), 7.73-7.64 (m, 3H), 7.24-7.19 (m, 1H), 7.06-7.04 (m, 2H), 3.70 (d, J=10.8 Hz, 1H), 3.62 (d, J=10.8 Hz, 1H), 2.80 (ddd, J=16.4, 8.7, 6.9 Hz, 1H), 2.70 (ddd, J=16.4, 9.1, 4.7 Hz, 1H), 2.23 (ddd, J=13.4, 9.1, 6.9 Hz, 1H), 2.07 (ddd, J=13.4, 8.7, 4.7 Hz, 1H), 2.07 (s, 1H). MS (ESI+) m/z=416 (M+H)⁺.

Example II-115 8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

To a solution of Example I-70D (25 mg, 0.12 mmol), EDAC (1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 46 mg, 0.24 mmol) and DMAP (4-dimethylaminopyridine) (16 mg, 0.13 mmol) in anhydrous dichloromethane (400 μL) was added naphthalene-1-sulfonamide (30 mg, 0.14 mmol). The solution was stirred at room temperature overnight and was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, using a 20 to 80% gradient of acetonitrile in 0.1% aqueous TFA] to give the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 12.44 (s, 1H), 8.70 (d, J=8.6 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.24 (dd, J=7.4, 1.2 Hz, 1H), 8.15-8.12 (m, 1H), 7.81 (ddd, J=8.6, 6.8, 1.4 Hz, 1H), 7.71 (ddd, J=8.2, 6.8, 1.1 Hz, 1H), 7.66 (dd, J=8.2, 7.4 Hz, 1H), 7.00 (dd, J=8.0, 7.6 Hz, 1H), 6.59 (d, J=7.6 Hz, 1H), 6.50 (d, J=8.0 Hz, 1H), 3.69-3.65 (m, 1H), 2.91 (s, 3H), 2.56-2.51 (m, 2H), 1.88-1.79 (m, 1H), 1.71-1.62 (m, 1H), 1.47-1.33 (m, 2H). MS (ESI+) m/z=396 (M+H)⁺.

Example II-128 5-chloro-8-hydroxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

To a solution of Example I-70 (192 mg, 0.44 mmol) in anhydrous dichloromethane (4 mL) at −15° C. under nitrogen was added dropwise 1 M BBr₃ in CHCl₂ (1.3 mL, 1.3 mmol). After two hours, the cold bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled with an ice bath and quenched first with methanol (200 μL) and then with 1 M aqueous KH₂PO₄ (1 mL). Ethyl acetate and heptane were added and the aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were dried (Na₂SO₄), filtered and concentrated to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.04 (bs, 1H), 8.51 (dd, J=7.4, 1.2 Hz, 1H), 8.40-8.36 (m, 1H), 8.12 (d, J=8.2 Hz, 1H), 7.98-7.94 (m, 1H), 7.64-7.56 (m, 3H), 7.16-7.11 (m, 1H), 6.52 (d, J=8.5 Hz, 1H), 3.75-3.71 (m, 1H), 2.72-2.62 (m, 1H), 2.57-2.46 (m, 1H), 2.03? (m, 1H), 1.69-1.55 (m, 3H). MS (ESI+) m/z 416 (M+H)⁺.

Example III-111 4-chloro-N-(naphthalene-1-sulfonyl)-1-[2-(pyrrolidin-1-yl)ethyl]-2,3-dihydro-1H-indene-1-carboxamide

Example I-16A (29 mg, ≤60 μmol) was dissolved into tetrahydrofuran (300 μL), treated with two drops of 2 M aqueous HCl, stirred at room temperature for 30 minutes and concentrated. The residue was dissolved into buffer (300 μL) (prepared from 3.6 g sodium acetate trihydrate, 4.6 mL acetic acid and sufficient methanol to bring the total volume to 100 mL) with pyrrolidine (7 μL, 84 μmol), then treated with sodium cyanoborohydride (6 mg, 95 μmol) and stirred at room temperature overnight. The reaction mixture was diluted with additional methanol and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-70% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound. ¹H NMR (501 MHz, CD₂Cl₂) δ ppm 8.81 (dd, J=8.7, 1.1 Hz, 1H), 8.26-8.24 (m, 1H), 7.96-7.93 (m, 1H), 7.92-7.89 (m, 1H), 7.63 (ddd, J=8.5, 6.8, 1.4 Hz, 1H), 7.56 (ddd, J=8.0, 6.8, 1.2 Hz, 1H), 7.48 (dd, J=8.2, 7.3 Hz, 1H), 7.07 (dd, J=7.4, 1.4 Hz, 1H), 6.89-6.86 (m, 1H), 6.86-6.82 (m, 1H), 3.5-3.1 (m, 4H), 3.00-2.96 (m, 2H), 2.91-2.84 (m, 1H), 2.80-2.70 (m, 2H), 2.24-2.16 (m, 4H), 2.11-1.96 (m, 2H), 1.84-1.77 (m, 1H). MS (ESI+) m/z 483 (M+H)⁺.

Example III-112 4-chloro-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Example I-16A (29 mg, ≤60 μmol) was dissolved into tetrahydrofuran (300 μL), treated with two drops of 2 M aqueous HCl, stirred at room temperature for 20 minutes and concentrated. The residue was dissolved into buffer (300 μL) (prepared from 3.6 g sodium acetate trihydrate, 4.6 mL acetic acid and sufficient methanol to bring the total volume to 100 mL) with (2-methoxyethyl)methylamine (9 μL, 83 μmol), then treated with sodium cyanoborohydride (6 mg, 95 μmol) and stirred at room temperature overnight. The reaction mixture was diluted with additional methanol and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-70% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound. ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 8.79-8.75 (m, 1H), 8.27-8.23 (m, 1H), 7.97-7.93 (m, 1H), 7.91-7.88 (m, 1H), 7.62-7.52 (m, 2H), 7.49-7.44 (m, 1H), 7.07 (dd, J=6.7, 2.2 Hz, 1H), 6.88-6.81 (m, 2H), 3.76-3.69 (m, 2H), 3.31 (s, 3H), 3.24-3.19 (m, 2H), 3.13-3.05 (m, 1H), 2.97-2.63 (m, 7H?), 2.22-2.12 (m, 1H), 1.93 (ddd, J=15.5, 8.3, 3.4 Hz, 1H), 1.84 (ddd, J=12.7, 7.9, 4.4 Hz, 1H). MS (ESI+) m/z 501 (M+H)⁺.

Example III-150 4-chloro-1-ethyl-N-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of the acid Example I-17A (27 mg, 0.12 mmol), EDAC (1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 46 mg, 0.24 mmol) and DMAP (4-dimethylaminopyridine) (16 mg, 0.13 mmol) in anhydrous dichloromethane (300 μL) was added N-methylnaphthalene-1-sulfonamide (31 mg, 0.14 mmol). The solution was stirred overnight at room temperature, concentrated and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 90% gradient of acetonitrile in 0.1% aqueous TFA] to give the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.36-8.31 (m, 2H), 8.17-8.13 (m, 1H), 8.13-8.09 (m, 1H), 7.79-7.68 (m, 3H), 7.34-7.31 (m, 1H), 7.20-7.14 (m, 1H), 6.60 (d, J=7.5 Hz, 1H), 3.12 (s, 3H), 3.08-2.93 (m, 2H), 2.44 (ddd, J=13.9, 10.1, 8.1 Hz, 1H), 2.05 (ddd, J=13.9, 8.5, 4.0 Hz, 1H), 1.66-1.51 (m, 2H), 0.29 (dd, J=7.3, 7.3 Hz, 3H). MS (ESI+) m/z 428 (M+H)⁺.

Example III-151 4-chloro-1-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide Example III-151A 1-(bromomethyl)-4-chloro-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of 1 M LiHMDS (lithium hexamethyldisilazide) in tetrahydrofuran (2.0 mL, 2.0 mmol) under nitrogen and cooled to 0° C. was added dropwise a solution of 4-chloro-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide (Example I-8, 308 mg, 0.80 mmol) in tetrahydrofuran (2 mL) over 12 minutes. After the reaction mixture had been stirred cold another 15 minutes, dibromomethane (85 μL, 1.2 mmol) was added dropwise, the bath was removed and the reaction mixture was stirred at room temperature overnight. The mixture was added to 1 M aqueous citric acid (1.5 mL) with a methyl tert-butyl ether rinse. The aqueous phase was separated and extracted with methyl tert-butyl ether and the combined organic phases were dried (Na₂SO₄), concentrated and filtered through silica (100% methyl tert-butyl ether) to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.55-8.51 (m, 1H), 8.30-8.22 (m, 2H), 8.16 (d, J=8.2 Hz, 1H), 7.98 (dd, J=6.3, 3.2 Hz, 1H), 7.67-7.59 (m, 3H), 7.28-7.24 (m, 1H), 7.09-7.04 (m, 1H), 7.00 (d, J=7.6 Hz, 1H), 3.58 (d, J=10.6 Hz, 1H), 3.54 (d, J=10.6 Hz, 1H), 3.04-2.82 (m, 2H), 2.34 (ddd, J=14.0, 8.8, 6.0 Hz, 1H), 2.23 (ddd, J=14.0, 8.9, 6.1 Hz, 1H). MS (ESI+) m/z 478/480 (M+H)⁺.

Example III-151B 4-chloro-1-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

Water (4 μL, 0.22 mmol) was added to 1 M KHMDS (potassium bis(trimethylsilyl)amide) in tetrahydrofuran (200 μL, 0.2 mmol) under nitrogen. To the resulting suspension was added a solution of Example III-151A (29 mg, 61 μmol) in dimethyl sulfoxide (150 μL) and the mixture was stirred more than 70 minutes before additional 1 M KHMDS in tetrahydrofuran (80 μL, 0.08 mmol) was added, followed by iodomethane (37.5 μL, 0.60 mmol). The reaction mixture was stirred vigorously overnight, quenched with four drops of 1 M aqueous citric acid, and stirred 90 minutes. The tetrahydrofuran was removed by evaporation and the remaining suspension was diluted with acetonitrile, filtered through a PTFE syringe filter and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 90% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.58 (d, J=8.5 Hz, 1H), 8.21-8.18 (m, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.98-7.94 (m, 1H), 7.71-7.65 (m, 1H), 7.65-7.59 (m, 1H), 7.54-7.49 (m, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.01-6.95 (m, 1H), 6.86 (d, J=7.5 Hz, 1H), 3.57 (s, 3H), 3.33 (d, J=12.9 Hz, 1H), 3.08 (d, J=12.9 Hz, 1H), 3.06-2.97 (m, 1H), 2.90 (ddd, J=16.9, 8.7, 6.2 Hz, 1H), 2.50 (ddd, J=13.5, 9.1, 6.2 Hz, 1H), 2.21 (ddd, J=13.5, 8.8, 5.5 Hz, 1H). MS (ESI+) m/z 430 (M+H)⁺.

Example III-155 4-chloro-1-(cyanomethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide

To a solution of 1 M LiHMDS (lithium bis(trimethylsilyl)amide) in tetrahydrofuran (280 μL, 0.28 mmol) under nitrogen and cooled to 0° C. was added dropwise a solution of Example I-8 (44 mg, 0.11 mmol) in tetrahydrofuran (280 μL) over 13 minutes. After the reaction mixture had been stirred cold another 15 minutes, iodoacetonitrile (12.4 μL, 0.17 mmol) was added dropwise, the bath was removed and the reaction mixture was stirred at room temperature for one day. The mixture was quenched with 1 M aqueous citric acid (200 μL) and extracted several times with methyl tert-butyl ether. The combined organic phases were dried (Na₂SO₄), filtered, concentrated and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 10 to 70% gradient of acetonitrile in 0.1% aqueous TFA] to give the impure product which was repurified by chromatography on silica (20 to 25% (200:1:1 ethyl acetate/water/formic acid)/heptane) to give the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.47-8.43 (m, 1H), 8.34-8.29 (m, 2H), 8.14-8.11 (m, 1H), 7.75-7.62 (m, 3H), 7.39-7.36 (m, 1H), 7.16-7.11 (m, 1H), 6.77 (d, J=7.3 Hz, 1H), 3.05-2.93 (m, 2H), 2.93-2.91 (m, 2H), 2.5-2.41 (m, 1H), 2.08-2.00 (m, 1H). MS (ESI+) m/z 442 (M+NH₄)⁺.

Example III-157 8-chloro-1-cyano-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Example III-157A phenyl 8-chloro-1-cyano-1,2,3,4-tetrahydronaphthalene-1-carboxylate

To 1 M LiHMDS (lithium bis(trimethylsilyl)amide) in tetrahydrofuran (1.3 mL, 1.3 mmol) under nitrogen and cooled to 0° C. was added dropwise over seven minutes a solution of Example I-2A (192 mg, 1.0 mmol) in anhydrous tetrahydrofuran (2 mL). The reaction mixture was stirred cold for 15 minutes and then cannulated dropwise into a solution of phenyl chloroformate (190 μL, 1.5 mmol) in tetrahydrofuran (3.0 mL) cooled to −78° C. After 15 minutes near −78° C., the temperature was permitted to rise to 0° C. over 50 minutes. The bath was removed. The reaction mixture was stirred 30 minutes, quenched with trifluoroacetic acid (100 μL) and concentrated. The residue was partitioned between chloroform and water and the separated aqueous phase was extracted with chloroform. The combined organic phases were washed with dilute brine, dried (Na₂SO₄), filtered, concentrated and chromatographed on silica (20 to 60% CH₂Cl₂/heptane) to give the title compound. ¹H NMR (500 MHz, CD₂Cl₂) δ ppm 7.45-7.40 (m, 2H), 7.37 (ddt, J=7.9, 1.4, 0.7 Hz, 1H), 7.33-7.28 (m, 2H), 7.21-7.18 (m, 1H), 7.17-7.14 (m, 2H), 2.97-2.94 (m, 2H), 2.84-2.79 (m, 1H), 2.43 (ddd, J=13.4, 11.9, 2.8 Hz, 1H), 2.17-2.10 (m, 1H), 2.07-1.98 (m, 1H). MS (ESI+) m/z 329 (M+NH₄)⁺.

Example III-157B 8-chloro-1-cyano-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

A solution of naphthalene-1-sulfonamide (63 mg, 0.30 mmol) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 45 μL, 0.30 mmol) in anhydrous N-methylmorpholine (1.0 mL) was added to the phenyl ester (Example III-157A, 63 mg, 0.20 mmol) under nitrogen with an N-methylmorpholine (300 μL) rinse. The reaction mixture was stirred at room temperature overnight, and heated at 60° C. for 30 minutes and at 100° C. for two hours. Sodium 1,2,4-triazolide (18 mg, 0.2 mmol) was added and the reaction mixture was heated again at 100° C. for two hours, brought to room temperature, concentrated and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 10 to 70% gradient of acetonitrile in 0.1% aqueous TFA] to give the title compound. ¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ ppm 8.61-8.55 (m, 1H), 8.29-8.24 (m, 2H), 8.12-8.08 (m, 1H), 7.71-7.63 (m, 3H), 7.39-7.29 (m, 1H), 7.23-7.18 (m, 2H), 2.92-2.73 (m, 2H), 2.27-2.19 (m, 1H), 2.03-1.77 (m, 2H), 1.61-1.51 (m, 1H). MS (ESI+) m/z 442 (M+NH₄)⁺.

Example N-(benzenesulfonyl)-4-chloro-1- II-1 methyl-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-1-methyl-N-(2- ¹H NMR (400 MHz, CDCl₃) δ ppm II-2 methylbenzene-1-sulfonyl)-2,3- 8.20-8.17 (m, 1H), 7.73-7.67 (m, 1H), 7.59-7.54 (m, 1H), dihydro-1H-indene-1-carboxamide 7.46-7.41 (m, 1H), 7.36-7.24 (m, 2H), 7.08-7.05 (m, 1H), 3.07-3.02 (m, 2H), 2.59-2.48 (m, 1H), 2.48 (s, 3H), 2.14-2.07 (m, 1H), 1.47 (s, 3H). MS (ESI+) m/z 434 (M + H)⁺. Example 4-chloro-N-(2-methylbenzene-1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.59 (s, II-3 sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 7.95-7.92 (m, 1H), 7.59-7.54 (m, 1H), carboxamide 7.43-7.39 (m, 2H), 7.29-7.23 (m, 1H), 7.23-7.20 (m, 2H), 4.13 (dd, J = 5.5, 8.5 Hz, 1H), 2.97-2.80 (m, 2H), 2.63 (s, 3H), 2.32-2.08 (m, 2H). MS (ESI+) m/z 350 (M + H)⁺. Example (1S)-6-chloro-1-methyl-N-(2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-4 methylbenzene-1-sulfonyl)-2,3- ppm 7.93 (dd, J = 7.9, 1.3 Hz, 1H), 7.58 (td, J = 7.5, dihydro-1H-indene-1-carboxamide 1.5 Hz, 1H), 7.46-7.36 (m, 2H), 7.30-7.12 (m, 3H), 2.91-2.70 (m, 2H), 2.52-2.42 (m, 4H), 2.03-1.91 (m, 1H), 1.42 (s, 3H). MS (APCI+) m/z 364.1 (M + H)⁺. Example (1R)-6-chloro-1-methyl-N-(2- ¹NMR (400 MHz, DMSO-d₆) δ ppm 12.03 (s, II-5 methylbenzene-1-sulfonyl)-2,3- 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.57 (dd, J = 7.2, 7.2 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.40 (dd, J = 7.7, 12.7 Hz, 2H), 7.23 (d, J = 3.5 Hz, 3H), 3.32 (s, 3H), 2.88-2.71 (m, 2H), 2.48-2.40 (m, 1H), 2.01-1.92 (m, 1H), 1.43 (s, 3H). MS (ESI+) m/z 364 (M + H)⁺. Example 4-chloro-N-(2-chlorobenzene-1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.93 (s, II-6 sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 3.8 Hz, carboxamide 2H), 7.60-7.55 (m, 1H), 7.29-7.19 (m, 3H), 4.18 (dd, J = 5.7, 8.5 Hz, 1H), 2.93-2.85 (m, 2H), 2.35-2.24 (m, 1H), 2.19-2.09 (m, 1H). MS (ESI+) m/z 370 (M + H)⁺. Example N-(2-methylbenzene-1-sulfonyl)- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-7 1,2,3,4-tetrahydronaphthalene-1- ppm 12.44 (s, 1H), 7.93 (dd, J = 7.9, 1.3 Hz, 1H), carboxamide 7.57 (td, J = 7.5, 1.4 Hz, 1H), 7.46-7.36 (m, 2H), 7.15-6.99 (m, 3H), 6.88-6.78 (m, 1H), 3.79 (t, J = 6.5 Hz, 1H), 2.65-2.60 (m, 5H), 1.91 (ddt, J = 14.5, 6.1, 3.3 Hz, 1H), 1.84-1.69 (m, 2H), 1.59-1.54 (m, 1H). MS (APCI+) m/z 330.1 (M + H)⁺. Example 5-methoxy-N-(2-methylbenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-8 sulfonyl)-1,2,3,4- ppm 7.93 (dd, J = 8.0, 1.3 Hz, 1H), 7.59 (td, J = 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.48-7.35 (m, 2H), 7.04 (t, J = 8.0 Hz, carboxamide 1H), 6.78 (dd, J = 8.3, 1.1 Hz, 1H), 6.48-6.40 (m, 1H), 3.77 (d, J = 12.4 Hz, 1H), 3.73 (s, 3H), 2.63 (s, 3H), 2.48 (t, J = 6.4 Hz, 2H), 1.92-1.50 (m, 4H). MS (APCI+) m/z 360.2 (M + H)⁺. Example 5,6-dimethoxy-N-(2-methylbenzene- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-9 1-sulfonyl)-1,2,3,4- ppm 7.93 (dd, J = 8.0, 1.4 Hz, 1H), 7.59 (td, J = 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.48-7.38 (m, 2H), 6.80 (d, J = 8.5 Hz, carboxamide 1H), 6.57 (dd, J = 8.4, 0.8 Hz, 1H), 3.79-3.70 (m, 4H), 3.64 (s, 3H), 2.63 (s, 3H), 2.57 (t, J = 6.5 Hz, 2H), 1.91-1.48 (m, 4H). MS (APCI+) m/z 390.1 (M + H)⁺. Example 8-chloro-N-(2-methylbenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-10 sulfonyl)-1,2,3,4- ppm 7.91 (dd, J = 7.9, 1.4 Hz, 1H), 7.58 (td, J = 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.46-7.33 (m, 2H), carboxamide 7.19-7.10 (m, 2H), 7.10-7.03 (m, 1H), 3.93 (t, J = 5.1 Hz, 1H), 2.75-2.60 (m, 5H), 2.02-1.89 (m, 2H), 1.72-1.60 (m, 1H), 1.52-1.37 (m, 1H). MS (APCI+) m/z 364.1 (M + H)⁺. Example N-(2-methylbenzene-1-sulfonyl)-2,3- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-11 dihydro-1H-indene-1-carboxamide ppm 7.97-7.88 (m, 1H), 7.58 (td, J = 7.4, 1.4 Hz, 1H), 7.46-7.37 (m, 2H), 7.26-7.09 (m, 4H), 4.03 (dd, J = 8.4, 5.7 Hz, 1H), 2.98-2.75 (m, 2H), 2.64 (s, 3H), 2.28-2.15 (m, 1H), 2.13-2.02 (m, 1H). MS (APCI+) m/z 316.2 (M + H)⁺. Example 6-fluoro-N-(2-methylbenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-12 sulfonyl)-1,2,3,4- ppm 7.93 (dd, J = 8.0, 1.3 Hz, 1H), 7.59 (td, J = 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.48-7.37 (m, 2H), carboxamide 7.00-6.82 (m, 3H), 3.78 (t, J = 6.3 Hz, 1H), 2.72-2.60 (m, 5H), 1.98-1.74 (m, 2H), 1.74-1.52 (m, 2H). MS (APCI+) m/z 348.1 (M + H)⁺. Example (1R)-5-methoxy-N-(2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-13 methylbenzene-1-sulfonyl)-1,2,3,4- ppm 7.93 (dd, J = 8.0, 1.4 Hz, 1H), 7.59 (td, J = 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.48-7.37 (m, 2H), 7.04 (t, J = 8.0 Hz, carboxamide 1H), 6.80-6.74 (m, 1H), 6.44 (d, J = 7.7 Hz, 1H), 3.80-3.75 (m, 1H), 3.73 (s, 3H), 2.63 (s, 3H), 2.48 (t, J = 6.5 Hz, 2H), 1.93-1.46 (m, 4H). MS (APCI+) m/z 360.1 (M + H)⁺. Example (1S)-N-(2-methylbenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-14 sulfonyl)-1,2,3,4- ppm 7.94 (dd, J = 8.0, 1.4 Hz, 1H), 7.59 (td, J = 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.48-7.37 (m, 2H), carboxamide 7.19-6.98 (m, 3H), 6.87-6.75 (m, 1H), 3.79 (t, J = 6.4 Hz, 1H), 2.68-2.61 (m, 5H), 2.00-1.85 (m, 1H), 1.85-1.66 (m, 2H), 1.65-1.51 (m, 1H). MS (APCI+) m/z 330.2 (M + H)⁺. Example 6,7-dimethoxy-N-(2-methylbenzene- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-15 1-sulfonyl)-1,2,3,4- ppm 7.95 (dd, J = 8.2, 1.3 Hz, 1H), 7.58 (td, J = 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.42 (d, J = 7.7 Hz, 2H), 6.63 (s, carboxamide 1H), 6.33 (s, 1H), 3.72-3.66 (m, 4H), 3.56 (s, 3H), 2.64 (s, 3H), 2.61-2.54 (m, 2H), 1.95-1.68 (m, 3H), 1.61-1.46 (m, 1H). MS (APCI+) m/z 390.1 (M + H)⁺. Example 4-methoxy-N-(2-methylbenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-16 sulfonyl)-2,3-dihydro-1H-indene-2- ppm 7.99-7.91 (m, 1H), 7.59 (td, J = 7.5, 1.4 Hz, carboxamide 1H), 7.43 (t, J = 7.2 Hz, 2H), 7.12 (t, J = 7.8 Hz, 1H), 6.76 (dd, J = 13.2, 7.8 Hz, 2H), 3.75 (s, 3H), 3.40-3.25 (m, 1H), 3.20-2.99 (m, 2H), 2.92 (dd, J = 16.2, 6.8 Hz, 1H), 2.78 (dd, J = 16.3, 6.6 Hz, 1H), 2.62 (s, 3H). MS (APCI+) m/z 346.2 (M + H)⁺. Example (1R)-N-(2-methylbenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-17 sulfonyl)-1,2,3,4- ppm 7.94 (dd, J = 8.0, 1.3 Hz, 1H), 7.59 (td, J = 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.48-7.37 (m, 2H), carboxamide 7.19-6.98 (m, 3H), 6.87-6.75 (m, 1H), 3.79 (t, J = 6.4 Hz, 1H), 2.76-2.58 (m, 5H), 2.00-1.66 (m, 3H), 1.65-1.53 (m, 1H). MS (APCI+) m/z 330.2 (M + H)⁺. Example (1S)-6-methoxy-1-methyl-N-(2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-18 methylbenzene-1-sulfonyl)-2,3- ppm 7.93 (dd, J = 8.0, 1.3 Hz, 1H), 7.57 (td, J = 7.5, dihydro-1H-indene-1-carboxamide 1.4 Hz, 1H), 7.45-7.35 (m, 2H), 7.19-7.07 (m, 1H), 6.82-6.73 (m, 2H), 3.71 (d, J = 5.2 Hz, 3H), 2.79-2.71 (m, 2H), 2.52-2.47 (m, 4H), 1.98-1.84 (m, 1H), 1.41 (s, 3H). MS (APCI+) m/z 360.2 (M + H)⁺. Example 7-chloro-1-methyl-N-(2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-19 methylbenzene-1-sulfonyl)-2,3- ppm 7.97 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.63-7.49 (m, 1H), 7.49-7.36 (m, 2H), 7.32-7.12 (m, 2H), 3.12-2.91 (m, 2H), 2.44-2.31 (m, 4H), 1.99-1.87 (m, 1H), 1.27 (s, 3H). MS (APCI+) m/z 364.1 (M + H)⁺. Example 4,5-difluoro-1-methyl-N-(2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-20 methylbenzene-1-sulfonyl)-2,3- ppm 7.93 (dd, J = 7.9, 1.3 Hz, 1H), 7.58 (td, J = 7.5, dihydro-1H-indene-1-carboxamide 1.4 Hz, 1H), 7.42 (ddd, J = 10.3, 6.2, 1.9 Hz, 2H), 7.29-7.17 (m, 1H), 6.98-6.89 (m, 1H), 3.02-2.80 (m, 2H), 2.51 (s, 4H), 2.12-1.98 (m, 1H), 1.39 (s, 3H). MS (APCI+) m/z 366.1 (M + H)⁺. Example 1-methyl-N-(2-methylbenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-21 sulfonyl)-2,3-dihydro-1H-indene-1- ppm 7.92 (dd, J = 8.0, 1.3 Hz, 1H), 7.57 (td, J = 7.5, carboxamide 1.4 Hz, 1H), 7.48-7.35 (m, 2H), 7.28-7.10 (m, 4H), 3.01-2.75 (m, 2H), 2.53-2.43 (m, 4H), 1.98-1.86 (m, 1H), 1.39 (s, 3H). MS (APCI+) m/z 330.2 (M + H)⁺. Example 1,5-dimethyl-N-(2-methylbenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-22 sulfonyl)-2,3-dihydro-1H-indene-1- ppm 7.91 (dd, J = 7.8, 1.3 Hz, 1H), 7.63-7.46 (m, carboxamide 1H), 7.45-7.35 (m, 2H), 7.09-6.95 (m, 3H), 2.91-2.70 (m, 2H), 2.53-2.34 (m, 4H), 2.26 (s, 3H), 1.95-1.83 (m, 1H), 1.36 (s, 3H). MS (APCI+) m/z 344.2 (M + H)⁺. Example 4-methoxy-N-(2-methylbenzene-1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.58 (s, II-23 sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 7.98 (d, J = 7.1 Hz, 1H), 7.64-7.59 (m, 1H), carboxamide 7.48-7.42 (m, 2H), 7.20 (dd, J = 7.8, 7.8 Hz, 1H), 6.87 (dd, J = 7.8, 16.4 Hz, 2H), 4.08 (dd, J = 5.7, 8.2 Hz, 1H), 3.80 (s, 3H), 2.90-2.71 (m, 2H), 2.69 (s, 3H), 2.28-2.11 (m, 2H). MS (ESI+) m/z 346 (M + H)⁺. Example N-(2-ethylbenzene-1-sulfonyl)-4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.62 (s, II-24 methoxy-2,3-dihydro-1H-indene-1- 1H), 7.98 (d, J = 8.1 Hz, 1H,), 7.66 (dd, J = 7.6, 7.6 Hz, carboxamide 1H,), 7.52 (d, J = 7.6 Hz, 1H,), 7.45 (dd, J = 7.5, 7.5 Hz, 1H,), 7.20 (dd, J = 7.8, 7.8 Hz, 1H,), 6.87 (dd, J = 8.0, 12.3 Hz, 2H), 4.07 (dd, J = 6.9, 6.9 Hz, 1H,), 3.80 (s, 3H), 3.18-3.03 (m, 2H), 2.90-2.72 (m, 2H), 2.26-2.12 (m, 2H), 1.30 (dd, J = 7.5, 7.5 Hz, 3H). MS (ESI+) m/z 360 (M + H)⁺. Example 4-chloro-N-(2-ethylbenzene-1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.69 (s, II-25 sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 7.98 (dd, J = 1.1, 8.0 Hz, 1H), 7.70-7.65 (m, carboxamide 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.45 (dd, J = 7.7, 7.7 Hz, 1H), 7.33-7.25 (m, 3H), 4.17 (dd, J = 5.7, 8.5 Hz, 1H), 3.16-3.00 (m, 2H), 2.99-2.87 (m, 2H), 2.36-2.14 (m, 2H), 1.30 (dd, J = 7.5, 7.5 Hz, 3H). MS (ESI+) m/z 364 (M + H)⁺. Example 4-chloro-N-(3-chlorobenzene-1- II-26 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-N-(4-chlorobenzene-1- II-27 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-N-(2-fluorobenzene-1- II-28 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example (1S)-4-chloro-N-(2-methylbenzene- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.15 (1H, II-29 1-sulfonyl)-2,3-dihydro-1H-indene- s), 7.78-7.75 (1H, m), 7.29-7.22 (2H, m), 1-carboxamide 7.19-7.09 (4H, m), 3.80-3.72 (1H, m), 2.96-2.89 (5H, m), 2.34-2.20 (1H, m), 2.12-2.02 (1H, m), 1.16 (dd, J = 7.3, 7.3 Hz, 6H). MS (ESI+) m/z 350 (M + H)⁺. Example N-(2-chlorobenzene-1-sulfonyl)-4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.90 (s, II-30 methoxy-2,3-dihydro-1H-indene-1- 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 3.5 Hz, carboxamide 2H), 7.64-7.58 (m, 1H), 7.20 (dd, J = 8.0, 8.0 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.14-4.07 (m, 1H), 3.80 (s, 3H), 2.90-2.71 (m, 2H), 2.31-2.13 (m, 2H). MS (ESI−) m/z 364 (M − H)⁻. Example 4-methoxy-N-(2-nitrobenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-31 sulfonyl)-2,3-dihydro-1H-indene-1- ppm 8.22-8.11 (m, 1H), 8.04-7.97 (m, 1H), carboxamide 7.96-7.81 (m, 2H), 7.14 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.14-4.04 (m, 1H), 3.75 (s, 3H), 2.88-2.65 (m, 2H), 2.29-2.08 (m, 2H). MS (APCI+) m/z 377 (M + H)⁺. Example 4-chloro-1-ethyl-N-(2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.94 (s, II-32 methylbenzene-1-sulfonyl)-2,3- 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.56 (dd, J = 7.0, 7.0 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.40 (dd, J = 7.7, 17.4 Hz, 2H), 7.29 (d, J = 6.4 Hz, 2H), 7.27-7.21 (m, 1H), 2.85 (dd, J = 7.2, 7.2 Hz, 2H), 2.49-2.39 (m, 1H), 2.11-2.03 (m, 2H), 1.78-1.69 (m, 1H), 0.67 (dd, J = 7.3, 7.3 Hz, 3H). MS (ESI+) m/z 378 (M + H)⁺. Example 4-bromo-N-(2-methylbenzene-1- ¹H NMR (400 MHz, CDCl₃) δ ppm 8.24-8.24 (m, II-33 sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.54-7.50 (m, 1H), carboxamide 7.43-7.35 (m, 2H), 7.31 (d, J = 7.7 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.08 (dd, J = 7.7, 7.7 Hz, 1H), 4.05 (dd, J = 6.2, 8.8 Hz, 1H), 3.11-2.89 (m, 2H), 2.58 (s, 3H), 2.48-2.37 (m, 1H), 2.31-2.21 (m, 1H). MS (ESI−) m/z 392 (M − H)⁻. Example 4-(3,6-dihydro-2H-pyran-4-yl)-N-(2- ¹H NMR 400 MHz (DMSO-d₆) δ ppm II-34 methylbenzene-1-sulfonyl)-2,3- 7.89-7.87 (m, 1H), 7.47 (t, j = 6.6 Hz, 1H), 7.35-7.30 (m, dihydro-1H-indene-1-carboxamide 2H), 7.17-7.01 (3H, m), 5.80 (m, 1H), 4.18-4.16 (2H, m), 3.90 (t, J = 7.3 Hz, 1H), 3.77 (t, J = 5.6 Hz, 2H), 2.98-2.76 (m, 2H), 2.58 (s, 3H), 2.36-2.31 (m, 2H), 2.13-2.06 (m, 2H). MS (ESI−) m/z 398.2 (M + H)⁻. Example 4-cyclobutyl-N-(2-methylbenzene-1- II-35 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- ¹H NMR (400 MHz, CDCl₃) δ ppm 8.31-8.27 (m, II-36 phenyl-2,3-dihydro-1H-indene-1- 1H), 8.18 (dd, J = 1.2, 8.0 Hz, 1H), 7.55-7.50 (m, carboxamide 1H), 7.43-7.29 (m, 9H), 7.18 (dd, J = 4.3, 4.3 Hz, 1H), 4.02 (dd, J = 6.2, 8.6 Hz, 1H), 3.13-3.04 (m, 1H), 2.99-2.90 (m, 1H), 2.59 (s, 3H), 2.45-2.35 (m, 1H), 2.29-2.19 (m, 1H). MS (ESI+) m/z 392 (M + H)⁺. Example 4-methoxy-N-[2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.82 (s, II-37 (trifluoromethyl)benzene-1- 1H), 8.31-8.27 (m, 1H), 8.04-8.00 (m, 1H), sulfonyl]-2,3-dihydro-1H-indene-1- 7.93-7.90 (m, 2H), 7.14 (dd, J = 7.8, 7.8 Hz, 1H), carboxamide 6.82 (dd, J = 7.9, 14.6 Hz, 2H), 4.06 (dd, J = 5.5, 8.3 Hz, 1H), 3.75 (s, 3H), 2.86-2.67 (m, 2H), 2.19-2.08 (m, 2H). MS (ESI+) m/z 400 (M + H)⁺. Example N-(2-fluorobenzene-1-sulfonyl)-4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.88 (s, II-38 methoxy-2,3-dihydro-1H-indene-1- 1H), 7.93-7.87 (m, 1H), 7.80-7.74 (m, 1H), carboxamide 7.51-7.40 (m, 2H), 7.15 (dd, J = 7.8, 7.8 Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 4.05 (dd, J = 5.9, 8.2 Hz, 1H), 3.75 (s, 3H), 2.85-2.67 (m, 2H), 2.22-2.08 (m, 2H). MS (ESI+) m/z 350 (M + H)⁺. Example N-(2-bromobenzene-1-sulfonyl)-4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm II-39 methoxy-2,3-dihydro-1H-indene-1- 12.89-12.87 (m, 1H), 8.12-8.09 (m, 1H), 7.87 (dd, J = 1.8, carboxamide 7.3 Hz, 1H), 7.64-7.55 (m, 2H), 7.15 (dd, J = 7.8, 7.8 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 4.09 (dd, J = 5.8, 8.2 Hz, 1H), 3.75 (s, 3H), 2.85-2.67 (m, 2H), 2.27-2.07 (m, 2H). MS (ESI+) m/z 410 (M + H)⁺. Example N-(2-methylbenzene-1-sulfonyl)-4- ¹H NMR (400 MHz, CDCl₃) δ ppm 8.15 (d, J = 8.0 Hz, II-40 [(propan-2-yl)oxy]-2,3-dihydro-1H- 1H), 7.51 (dd, J = 7.5, 7.5 Hz, 1H), 7.37 (dd, J = 7.7, indene-1-carboxamide 7.7 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.17 (dd, J = 7.9, 7.9 Hz, 1H), 6.76 (dd, J = 7.8, 11.7 Hz, 2H), 4.61-4.51 (m, 1H), 3.94 (dd, J = 5.5, 9.2 Hz, 1H), 2.99-2.81 (m, 2H), 2.52 (s, 3H), 2.47-2.37 (m, 1H), 2.28-2.18 (m, 1H), 1.35 (dd, J = 6.0, 10.3 Hz, 6H). MS (ESI−) m/z 372 (M − H)⁻. Example 7-bromo-4-methoxy-N-(2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.50 (s, II-41 methylbenzene-1-sulfonyl)-2,3- 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.55 (dd, J = 7.3, 7.3 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.39 (dd, J = 8.3, 8.3 Hz, 2H), 7.24 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 4.04 (dd, J = 3.6, 9.5 Hz, 1H), 3.75 (s, 3H), 2.87-2.80 (m, 2H), 2.65 (s, 3H), 2.45-2.33 (m, 1H), 1.98 (ddd, J = 4.8, 8.2, 17.1 Hz, 1H). MS (ESI−) m/z 422 (M − H)⁻. Example 4-(2-methoxypyridin-4-yl)-N-(2- II-42 methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 5-methoxy-N-(quinoline-8-sulfonyl)- ¹H NMR (400 MHz, Chloroform-d) δ ppm II-43 1,2,3,4-tetrahydronaphthalene-1- 8.79 (dd, J = 4.3, 1.8 Hz, 1H), 8.72 (s, 1H), 8.63 (dd, J = 7.4, carboxamide 1.5 Hz, 1H), 8.28 (dd, J = 8.4, 1.8 Hz, 1H), 8.12 (dd, J = 8.3, 1.5 Hz, 1H), 7.71 (dd, J = 8.2, 7.4 Hz, 1H), 7.54 (dd, J = 8.3, 4.2 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 6.81 (dd, J = 8.2, 1.1 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 3.90 (s, 3H), 3.65 (t, J = 5.2 Hz, 1H), 2.65-2.42 (m, 2H), 2.09 (d, J = 5.6 Hz, 1H), 1.86-1.71 (m, 1H), 1.37-1.17 (m, 2H). MS (APCI+) m/z 397 (M + H)⁺. Example (1R)-5-methoxy-1-methyl-N- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-44 (naphthalene-1-sulfonyl)-2,3- 8.58 (dd, J = 8.3, 1.4 Hz, 1H), 8.31-8.23 (m, 2H), dihydro-1H-indene-1-carboxamide 8.15-8.05 (m, 1H), 7.77-7.64 (m, 3H), 6.96 (d, J = 8.3 Hz, 1H), 6.77-6.68 (m, 1H), 6.63 (dd, J = 8.4, 2.6 Hz, 1H), 3.69 (s, 3H), 2.80-2.55 (m, 2H), 2.40-2.29 (m, 1H), 1.86-1.75 (m, 1H), 1.29 (s, 3H). MS (APCI+) m/z 396.0 (M + H)⁺. Example (1S)-5-methoxy-1-methyl-N- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-45 (naphthalene-1-sulfonyl)-2,3- ppm 8.62-8.54 (m, 1H), 8.27 (dd, J = 7.5, 5.9 Hz, dihydro-1H-indene-1-carboxamide 2H), 8.19-8.03 (m, 1H), 7.78-7.64 (m, 3H), 6.96 (d, J = 8.4 Hz, 1H), 6.78-6.68 (m, 1H), 6.62 (dd, J = 8.5, 2.5 Hz, 1H), 3.69 (s, 3H), 2.83-2.55 (m, 2H), 2.44-2.29 (m, 1H), 1.92-1.74 (m, 1H), 1.29 (s, 3H). MS (APCI+) m/z 396.0 (M + H)⁺. Example (1S)-4-methoxy-1-methyl-N- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-46 (naphthalene-1-sulfonyl)-2,3- ppm 8.62-8.54 (m, 1H), 8.31-8.23 (m, 2H), dihydro-1H-indene-1-carboxamide 8.19-8.03 (m, 1H), 7.75-7.65 (m, 3H), 7.07 (t, J = 7.9 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 3.73 (s, 3H), 2.76-2.55 (m, 2H), 2.48-2.29 (m, 1H), 1.92-1.74 (m, 1H), 1.28 (s, 3H). MS (APCI+) m/z 396.1 (M + H)⁺. Example 4-chloro-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (d, J = 8.4 Hz, II-47 sulfonyl)-1-[(pyrrolidin-1- 1H), 8.03 (dd, J = 7.3, 1.3 Hz, 1H), yl)methyl]-2,3-dihydro-1H-indene- 7.97 (d, J = 8.2 Hz, 1H), 7.93-7.90 (m, 1H), 1-carboxamide 7.53-7.42 (m, 3H), 7.22 (dd, J = 6.2, 2.7 Hz, 1H), 7.08-7.03 (m, 2H), 3.77 (d, J = 12.9 Hz, 1H), 3.19 (d, J = 12.9 Hz, 1H), 3.13-2.85 (m, 6H?), 2.65 (ddd, J = 13.2, 8.5, 5.0 Hz, 1H), 2.01 (ddd, J = 12.8, 8.5, 6.7 Hz, 1H), 1.78-1.64 (m, 4H). MS (ESI+) m/z 469 (M + H)⁺. Example 4-methoxy-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-48 sulfonyl)-2,3-dihydro-1H-indene-2- ppm 8.73-8.65 (m, 1H), 8.28 (dd, J = 7.4, 1.3 Hz, carboxamide 1H), 8.22 (dt, J = 8.5, 1.1 Hz, 1H, 8.10-8.03 (m, 1H), 7.78-7.70 (m, 1H), 7.69-7.60 (m, 2H), 7.09-6.99 (m, 1H), 6.67 (d, J = 7.9 Hz, 2H), 3.70 (s, 3H), 3.35-3.18 (m, 1H), 2.99 (dt, J = 16.3, 8.0 Hz, 2H), 2.83 (dd, J = 16.0, 7.1 Hz, 1H), 2.72 (dd, J = 16.3, 6.7 Hz, 1H). MS (APCI+) m/z 382.1 (M + H)⁺. Example 1-methyl-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-49 sulfonyl)-6-(trifluoromethoxy)-2,3- ppm 8.62-8.55 (m, 1H), 8.31-8.23 (m, 2H), dihydro-1H-indene-1-carboxamide 8.10 (dd, J = 7.9, 1.6 Hz, 1H), 7.75-7.63 (m, 3H), 7.24 (d, J = 8.3 Hz, 1H), 7.15-7.07 (m, 1H), 7.07-7.02 (m, 1H), 2.84-2.72 (m, 1H), 2.66-2.54 (m, 1H), 2.45-2.33 (m, 1H), 1.98-1.86 (m, 1H), 1.37 (s, 3H). MS (APCI+) m/z 450.0 (M + H)⁺. Example 8-bromo-5-hydroxy-N-(naphthalene- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.67 (s, II-50 1-sulfonyl)-1,2,3,4- 1H), 9.51 (bs, 1H), 8.68 (d, J = 8.7 Hz, 1H), tetrahydronaphthalene-1- 8.28 (d, J = 8.3 Hz, 1H), 8.24 (dd, J = 7.4, 1.2 Hz, 1H), carboxamide 8.11 (d, J = 7.9 Hz, 1H), 7.75 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.70-7.63 (m, 2H), 6.94 (d, J = 8.6 Hz, 1H), 6.53 (d, J = 8.6 Hz, 1H), 3.75 (dd, J = 6.3, 2.4 Hz, 1H), 2.52-2.44 (m, 1H), 2.22 (ddd, J = 17.5, 11.2, 6.1 Hz, 1H), 1.90 (d, J = 12.7 Hz, 1H), 1.73 (dddd, J = 13.5, 9.0, 6.5, 3.2 Hz, 1H), 1.49-1.40 (m, 1H), 1.10-0.97 (m, 1H). LC/MS (ESI+) m/z 460, 462 (M + H)⁺. Example 5,6-dimethoxy-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-51 sulfonyl)-1,2,3,4- ppm 8.65 (dd, J = 8.5, 1.1 Hz, 1H), 8.34-8.24 (m, tetrahydronaphthalene-1- 2H), 8.15 (d, J = 8.1 Hz, 1H), 7.87-7.78 (m, 1H), carboxamide 7.77-7.72 (m, 1H), 7.72-7.64 (m, 1H), 6.50 (d, J = 8.6 Hz, 1H), 6.33 (d, J = 8.3 Hz, 1H), 3.70-3.65 (m, 4H), 3.59 (s, 3H), 2.53-2.38 (m, 2H), 1.77-1.54 (m, 2H), 1.52-1.34 (m, 2H). MS (APCI+) m/z 426.0 (M + H)⁺. Example N-(naphthalene-1-sulfonyl)- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-52 2,3,7,8,9,10-hexahydronaphtho[1,2- ppm 8.65 (dd, J = 8.6, 1.0 Hz, 1H), 8.33-8.23 (m, b][1,4]dioxine-7-carboxamide 2H), 8.18-8.10 (m, 1H), 7.86-7.77 (m, 1H), 7.77-7.71 (m, 1H), 7.71-7.64 (m, 1H), 6.26 (d, J = 8.4 Hz, 1H), 6.10-6.03 (m, 1H), 4.19-4.13 (m, 2H), 4.13-4.04 (m, 2H), 3.62 (t, J = 6.2 Hz, 1H), 2.44-2.26 (m, 2H), 1.76-1.56 (m, 2H), 1.52-1.30 (m, 2H). MS (APCI+) m/z 424.0 (M + H)⁺. Example 6,7-dimethoxy-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-53 sulfonyl)-1,2,3,4- ppm 8.69-8.61 (m, 1H), 8.33-8.27 (m, 2H), tetrahydronaphthalene-1- 8.16-8.10 (m, 1H), 7.85-7.77 (m, 1H), carboxamide 7.73-7.67 (m, 2H), 6.54 (s, 1H), 5.95 (s, 1H), 3.72 (s, 3H), 3.66 (t, J = 6.3 Hz, 1H), 3.10 (s, 3H), 2.48 (t, J = 6.3 Hz, 2H), 1.86-1.73 (m, 1H), 1.73-1.61 (m, 1H), 1.60-1.48 (m, 1H), 1.46-1.34 (m, 1H). MS (APCI+) m/z 426.0 (M + H)⁺. Example 4-chloro-N-(2-chlorobenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-54 sulfonyl)-1-ethyl-2,3-dihydro-1H- ppm 8.07 (dd, J = 7.9, 1.6 Hz, 1H), 7.73-7.60 (m, indene-1-carboxamide 2H), 7.63-7.53 (m, 1H), 7.34-7.19 (m, 3H), 2.94-2.77 (m, 2H), 2.53-2.41 (m, 1H), 2.15-2.00 (m, 2H), 1.84-1.70 (m, 1H), 0.71 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z 398.0 (M + H)⁺. Example 4-chloro-1-ethyl-N-(2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-55 methoxybenzene-1-sulfonyl)-2,3- ppm 7.81 (dd, J = 7.8, 1.7 Hz, 1H), 7.65 (t, J = 7.9 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.36-7.22 (m, 3H), 7.18 (d, J = 8.5 Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H), 3.82 (s, 3H), 2.93-2.75 (m, 2H), 2.51-2.39 (m, 1H), 2.17-2.03 (m, 1H), 1.78-1.68 (m, 1H), 0.69 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 394.0 (M + H)⁺. Example 4-chloro-1-ethyl-N-[5-methyl-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-56 (propan-2-yl)benzene-1-sulfonyl]- ppm 7.70 (d, J = 1.9 Hz, 1H), 7.47-7.39 (m, 1H), 2,3-dihydro-1H-indene-1- 7.38-7.20 (m, 4H), 2.89 (dt, J = 29.5, 7.0 Hz, carboxamide 3H), 2.51-2.39 (m, 4H), 2.16-1.98 (m, 2H), 1.80-1.66 (m, 1H), 1.18 (d, J = 6.9 Hz, 6H), 0.71 (d, J = 7.4 Hz, 3H). MS (APCI+) m/z 420.0 (M + H)⁺. Example 4-chloro-N-[3-chloro-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-57 (methoxymethyl)benzene-1- ppm 7.98 (dd, J = 8.1, 1.2 Hz, 1H), 7.81 (dd, J = 8.1, sulfonyl]-1-ethyl-2,3-dihydro-1H- 1.2 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), indene-1-carboxamide 7.33-7.18 (m, 3H), 4.73 (q, J = 10.5 Hz, 2H), 3.34 (s, 3H), 2.93-2.82 (m, 2H), 2.52-2.40 (m, 1H), 2.12-1.90 (m, 2H), 1.83-1.69 (m, 1H), 0.68 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z 441.9 (M + H)⁺. Example 4-chloro-1-ethyl-N-(2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-58 fluorobenzene-1-sulfonyl)-2,3- ppm 7.89 (td, J = 7.7, 1.9 Hz, 1H), 7.81-7.71 (m, dihydro-1H-indene-1-carboxamide 1H), 7.48-7.37 (m, 2H), 7.33-7.20 (m, 3H), 2.94-2.77 (m, 2H), 2.50-2.38 (m, 1H), 2.15-2.01 (m, 2H), 1.81-1.67 (m, 1H), 0.69 (t, J = 7.3 Hz, 3H). MS (APO+) m/z 382.0 (M + H)⁺. Example 4-chloro-1-ethyl-N-(2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-59 phenoxybenzene-1-sulfonyl)-2,3- ppm 7.95 (dd, J = 8.0, 1.7 Hz, 1H), 7.67-7.57 (m, dihydro-1H-indene-1-carboxamide 1H), 7.49-7.38 (m, 2H), 7.36-7.17 (m, 5H), 7.00-6.92 (m, 2H), 6.92-6.85 (m, 1H), 2.92-2.74 (m, 2H), 2.49-2.37 (m, 1H), 2.13-1.99 (m, 2H), 1.83-1.69 (m, 1H), 0.73 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 456.0 (M + H)⁺. Example 4-chloro-1-ethyl-N-[2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-60 (trifluoromethoxy)benzene-1- ppm 8.02 (dd, J = 7.9, 1.7 Hz, 1H), 7.86-7.77 (m, sulfonyl]-2,3-dihydro-1H-indene-1- 1H), 7.63-7.50 (m, 2H), 7.33-7.19 (m, 3H), carboxamide 2.94-2.76 (m, 2H), 2.51-2.39 (m, 1H), 2.15-2.01 (m, 2H), 1.81-1.67 (m, 1H), 0.70 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 447.9 (M + H)⁺. Example 4-chloro-N-[2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-61 (difluoromethoxy)benzene-1- ppm 7.96 (dd, J = 8.0, 1.7 Hz, 1H), 7.74 (td, J = 7.8, sulfonyl]-1-ethyl-2,3-dihydro-1H- 1.8 Hz, 1H), 7.51-7.10 (m, 6H), indene-1-carboxamide 2.94-2.76 (m, 2H), 2.51-2.39 (m, 1H), 2.14-1.98 (m, 2H), 1.84-1.70 (m, 1H), 0.70 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 430.0 (M + H)⁺. Example 4-chloro-N-(2,5-dimethylbenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-62 sulfonyl)-1-ethyl-2,3-dihydro-1H- ppm 7.72-7.67 (m, 1H), 7.41-7.34 (m, 1H) indene-1-carboxamide 7.32-7.20 (m, 4H), 2.85 (t, J = 7.3 Hz, 2H), 2.44 (s, 4H), 2.32 (s, 3H), 2.15-1.99 (m, 2H), 1.80-1.66 (m, 1H), 1.05 (d, J = 6.1 Hz, 0H), 0.69 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 392.1 (M + H)⁺. Example 4-chloro-1-ethyl-N-[2-(2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-63 methoxyethoxy)benzene-1- ppm 7.82 (dd, J = 7.9, 1.7 Hz, 1H), 7.63 (t, J = 8.1 Hz, sulfonyl]-2,3-dihydro-1H-indene-1- 1H), 7.36-7.15 (m, 4H), 7.11 (t, J = 7.6 Hz, carboxamide 1H), 4.19 (t, J = 4.9 Hz, 2H), 3.75-3.68 (m, 2H), 3.32 (s, 3H), 2.86 (t, J = 7.3 Hz, 2H), 2.46 (dt, J = 14.2, 7.3 Hz, 1H), 2.14-1.96 (m, 2H), 1.81-1.70 (m, 1H), 0.68 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z 438.0 (M + H)⁺. Example N-([1,1′-biphenyl]-2-sulfonyl)-4- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-64 chloro-1-ethyl-2,3-dihydro-1H- ppm 8.02 (dd, J = 8.0, 1.4 Hz, 1H), 7.71-7.62 (m, indene-1-carboxamide 1H), 7.61-7.54 (m, 1H), 7.41-7.15 (m, 10H), 2.81 (t, J = 7.3 Hz, 2H), 2.25-2.20 (m, 1H), 1.99-1.86 (m, 1H), 1.71-1.62 (m, 1H), 0.68 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 440.0 (M + H)⁺. Example 4-chloro-1-ethyl-N-(naphthalene-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-65 sulfonyl)-2,3-dihydro-1H-indene-1- ppm 8.47 (s, 1H), 8.17-8.00 (m, 3H), 7.80 (dd, J = 8.7, carboxamide 1.9 Hz, 1H), 7.76-7.65 (m, 2H), 7.31-7.18 (m, 3H), 2.82 (t, J = 7.3 Hz, 2H), 2.48-2.38 (m, 1H), 2.11-1.93 (m, 2H), 1.72-1.62 (m, 1H), 0.62 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 414.0 (M + H)⁺. Example N-(benzenesulfonyl)-4-chloro-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-66 ethyl-2,3-dihydro-1H-indene-1- ppm 7.84 (d, J = 7.7 Hz, 2H), 7.71-7.64 (m, 1H), carboxamide 7.59 (t, J = 7.6 Hz, 2H), 7.32-7.19 (m, 3H), 2.84 (t, J = 7.3 Hz, 2H), 2.47-2.35 (m, 1H), 2.10-1.93 (m, 2H), 1.75-1.61 (m, 1H), 0.63 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z 364.1 (M + H)⁺. Example N-(2,1,3-benzothiadiazole-4- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-67 sulfonyl)-4-chloro-1-ethyl-2,3- ppm 8.48-8.34 (m, 1H), 8.34-8.26 (m, 1H), dihydro-1H-indene-1-carboxamide 7.91 (t, J = 8.0 Hz, 1H), 7.26-7.22 (m, 1H), 7.21-7.12 (m, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.52-2.44 (m, 1H), 2.1-1 1.97 (m, 2H), 1.75 1.49 (m, 1H), 0.58 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 422.0 (M + H)⁺. Example N-(naphthalene-1-sulfonyl)-2,3- ¹H NMR (501 MHz, DMSO-d₆) δ ppm 12.79 (s, II-68 dihydro-1H-indene-1-carboxamide 1H), 8.70 (dd, J = 8.6, 1.0 Hz, 1H), 8.27 (d, J = 7.5 Hz, 2H), 8.12 (dt, J = 8.2, 1.0 Hz, 1H), 7.83 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.12 (dt, J = 7.5, 1.0 Hz, 1H), 7.06 (tt, J = 7.5, 0.9 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.89 (td, J = 7.4, 1.2 Hz, 1H), 3.98 (dd, J = 8.3, 6.1 Hz, 1H), 2.86-2.68 (m, 2H), 2.16-2.08 (m, 1H), 1.98 (ddt, J = 12.8, 8.8, 6.4 Hz, 1H). MS (APCI+) m/z 352 (M + H)⁺. Example 4-chloro-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-69 sulfonyl)-1-[(oxolan-3-yl)methyl]- ppm 8.76-8.67 (m, 1H), 8.07-8.00 (m, 1H), 2,3-dihydro-1H-indene-1- 7.92 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), carboxamide 7.50-7.38 (m, 3H), 7.27-7.19 (m, 1H), 7.12-6.99 (m, 2H), 3.60-3.29 (m, 3H), 3.03-2.62 (m, 4H), 2.27-2.08 (m, 1H), 1.96-1.61 (m, 3H), 1.60-1.47 (m, 1H), 1.33-1.19 (m, 1H). MS (APCI+) m/z 469.9 (M + H)⁺. Example 4-chloro-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-70 sulfonyl)-1-[2-(1H-pyrazol-1- ppm 8.79-8.72 (m, 1H), 8.03 (dd, J = 7.3, 1.3 Hz, yl)ethyl]-2,3-dihydro-1H-indene-1- 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.87-7.81 (m, 1H), carboxamide 7.50-7.29 (m, 5H), 7.25-7.18 (m, 1H), 7.12-7.06 (m, 1H), 7.06-6.98 (m, 1H), 6.13 (t, J = 2.1 Hz, 1H), 3.99-3.81 (m, 2H), 2.92-2.79 (m, 1H), 2.78-2.68 (m, 1H), 2.67-2.58 (m, 1H), 2.51-2.39 (m, 1H), 2.03-1.94 (m, 1H), 1.79-1.67 (m, 1H). MS (APCI+) m/z 479.9 (M + H)⁺. Example 4-chloro-1-[(5-methoxypyridin-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-71 yl)methyl]-N-(naphthalene-1- ppm 8.74 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 7.3 Hz, sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 7.98-7.93 (m, 1H), 7.90 (d, J = 8.2 Hz, 1H), carboxamide 7.86 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.40-7.31 (m, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.09-6.99 (m, 2H), 6.74 (d, J = 1.8 Hz, 2H), 3.72 (s, 3H), 3.44 (d, J = 13.3 Hz, 1H), 2.90 (d, J = 13.4 Hz, 1H), 2.78-2.64 (m, 1H), 2.49-2.37 (m, 2H), 1.99-1.94 (m, 1H). MS (APCI+) m/z 506.9 (M + H)⁺. Example 4-chloro-1-[(2-methoxypyridin-4- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-72 yl)methyl]-N-(naphthalene-1- ppm 8.64 (d, J = 8.5 Hz, 1H), 8.16-8.11 (m, 1H), sulfonyl)-2,3-dihydro-1H-indene-1- 8.05 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), carboxamide 7.67 (d, J = 5.2 Hz, 1H), 7.58-7.50 (m, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.17-7.07 (m, 2H), 7.07-7.00 (m, 1H), 6.39 (dd, J = 5.2, 1.5 Hz, 1H), 6.28 (s, 1H), 3.73 (s, 3H), 3.28 (d, J = 13.5 Hz, 1H), 2.85 (d, J = 13.6 Hz, 1H), 2.81-2.68 (m, 1H), 2.51-2.38 (m, 2H), 1.95-1.84 (m, 1H). MS (APCI+) m/z 506.9 (M + H)⁺. Example 4-chloro-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-73 sulfonyl)-1-{[3- ppm 8.61 (d, J = 8.8 Hz, 1H), 8.11-8.06 (m, 1H), (trifluoromethyl)pyridin-2- 8.03-7.84 (m, 4H), 7.51-7.46 (m, 2H), yl]methyl}-2,3-dihydro-1H-indene- 7.38-7.33 (m, 1H). 7.21-7.07 (m, 3H), 7.00 (t, J = 7.7 Hz, 1-carboxamide 1H), 3.90 (d, J = 16.8 Hz, 1H), 3.24-3.19 (m, 1H), 2.96-2.61 (m, 3H), 1.95-1.83 (m, 1H). MS (APCI+) m/z 544.9 (M + H)⁺. Example 4-chloro-N-(2,3-dihydro-1,4- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-74 benzodioxine-5-sulfonyl)-1-ethyl- ppm 7.42-7.32 (m, 2H), 7.32-7.22 (m, 2H), 2,3-dihydro-1H-indene-1- 7.20-7.13 (m, 1H), 6.98 (t, J = 8.0 Hz, 1H), carboxamide 4.36-4.11 (m, 4H), 2.86 (t, J = 7.2 Hz, 2H), 2.52-2.43 (m, 1H), 2.20-2.01 (m, 2H), 1.81-1.65 (m, 1H), 0.73 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 422.0 (M + H)⁺. Example 4-bromo-N-(naphthalene-1- ¹H NMR (400 MHz, Chloroform-d) δ ppm II-75 sulfonyl)-2,3-dihydro-1H-indene-1- 8.60-8.43 (m, 3H), 8.16 (d, J = 8.2 Hz, 1H), 8.00 (dd, J = 7.5, carboxamide 1.6 Hz, 1H), 7.74-7.57 (m, 3H), 7.36 (dd, J = 6.4, 2.5 Hz, 1H), 6.91 (q, J = 5.2, 4.6 Hz, 2H), 3.97 (dd, J = 9.0, 6.3 Hz, 1H), 2.99-2.77 (m, 2H), 2.32 (dtd, J = 14.6, 8.8, 6.0 Hz, 1H), 2.12 (ddd, J = 13.3, 8.7, 6.4 Hz, 1H). MS (APCI+) m/z 430 (M + H)⁺. Example N-(4-bromonaphthalene-1-sulfonyl)- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-76 4-chloro-1-ethyl-2,3-dihydro-1H- ppm 8.68-8.60 (m, 1H), 8.33 (dd, J = 7.8, 1.7 Hz, indene-1-carboxamide 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.89-7.76 (m, 2H), 7.27-7.10 (m, 3H), 2.86-2.71 (m, 2H), 2.37-2.26 (m, 1H), 2.08-1.88 (m, 2H), 1.70-1.56 (m, 1H), 0.47 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 491.8 (M + H)⁺. Example 4-chloro-1-ethyl-N-(4- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-77 fluoronaphthalene-1-sulfonyl)-2,3- ppm 8.62 (d, J = 8.2 Hz, 1H), 8.33-8.24 (m, 1H), dihydro-1H-indene-1-carboxamide 8.24-8.16 (m, 1H), 7.81-7.73 (m, 2H), 7.52 (t, J = 9.2 Hz, 1H), 7.26-7.10 (m, 3H), 2.86-2.71 (m, 2H), 2.36-2.28 (m, 1H), 2.08-1.89 (m, 2H), 1.67-1.56 (m, 1H), 0.47 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 432.0 (M + H)⁺. Example N-(5-bromonaphthalene-1-sulfonyl)- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-78 4-chloro-1-ethyl-2,3-dihydro-1H- ppm 8.64 (d, J = 8.7 Hz, 1H), 8.46 (d, J = 8.6 Hz, indene-1-carboxamide 1H), 8.31 (d, J = 7.7 Hz, 1H), 8.00 (d, J = 7.4 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.23-7.08 (m, 3H), 2.75 (s, 2H), 2.41-2.26 (m, 1H), 2.04-1.93 (m, 1H), 1.92-1.87 (m, 1H), 1.63-1.54 (m, 1H), 0.48 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 491.8 (M + H)⁺. Example 4-chloro-1-ethyl-N-(5,6,7,8- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-79 tetrahydronaphthalene-1-sulfonyl)- ppm 7.86-7.75 (m, 1H), 7.48-7.21 (m, 5H), 2,3-dihydro-1H-indene-1- 3.05-2.73 (m, 6H), 2.53-2.38 (m, 1H), 2.23-1.94 (m, carboxamide 2H), 1.83-1.58 (m, 5H), 0.73 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z 418.0 (M + H)⁺. Example 4-chloro-N-(3,4-dihydroquinoline- ¹H NMR (501 MHz, CD₂Cl₂) δ ppm 7.71 (bs, 1H), II-80 1(2H)-sulfonyl)-1-ethyl-2,3-dihydro- 7.43-7.40 (m, 1H), 7.25 (dd, J = 8.0, 0.9 Hz, 1H), 1H-indene-1-carboxamide 7.16-7.13 (m, 1H), 7.12-7.03 (m, 3H), 6.78-6.75 (m, 1H), 4.02-3.92 (m, 2H), 2.85 (ddd, J = 16.9, 8.8, 5.6 Hz, 1H), 2.75-2.68 (m, 3H), 2.24 (ddd, J = 13.3, 8.7, 5.5 Hz, 1H), 2.05-1.95 (m, 3H), 1.80 (dq, J = 13.9, 7.4 Hz, 1H), 1.73 (dq, J = 13.9, 7.4 Hz, 1H), 0.65 (t, J = 7.4 Hz, 3H). MS (ESI+) m/z 419 (M + H)⁺. Example 4-chloro-1-(hydroxymethyl)-N- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.08 (bs, II-81 (naphthalene-1-sulfonyl)-2,3- 1H), 8.59-8.55 (m, 1H), 8.30-8.26 (m, 2H), dihydro-1H-indene-1-carboxamide 8.11-8.08 (m, 1H), 7.73-7.64 (m, 3H), 7.24-7.19 (m, 1H), 7.06-7.04 (m, 2H), 3.70 (d, J = 10.8 Hz, 1H), 3.62 (d, J = 10.8 Hz, 1H), 2.80 (ddd, J = 16.4, 8.7, 6.9 Hz, 1H), 2.70 (ddd, J = 16.4, 9.1, 4.7 Hz, 1H), 2.23 (ddd, J = 13.4, 9.1, 6.9 Hz, 1H), 2.07 (ddd, J = 13.4, 8.7, 4.7 Hz, 1H), 2.07 (s, 1H). MS (ESI+) m/z 416 (M + H)⁺. Example 4-cyclobutyl-N-(4- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-82 cyclobutylnaphthalene-1-sulfonyl)- ppm 8.65-8.58 (m, 1H), 8.24-8.17 (m, 1H), 1-ethyl-2,3-dihydro-1H-indene-1- 8.14-8.07 (m, 1H), 7.70-7.63 (m, 2H), 7.55 (d, carboxamide J = 7.7 Hz, 1H), 7.20-7.03 (m, 3H), 4.26-4.13 (m, 1H), 3.49-3.38 (m, 1H), 2.70-2.54 (m, 2H), 2.54-2.39 (m, 1H), 2.32-1.69 (m, 12H), 1.61-1.51 (m, 1H), 1.28-1.12 (m, 2H), 0.48 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 488.0 (M + H)⁺. Example 4-cyclobutyl-N-(5- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-83 cyclobutylnaphthalene-1-sulfonyl)- ppm 8.45 (d, J = 8.6 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1-ethyl-2,3-dihydro-1H-indene-1- 1H), 8.24 (d, J = 7.4 Hz, 1H), 7.74-7.59 (m, 2H), carboxamide 7.52 (d, J = 7.2 Hz, 1H), 7.23-7.02 (m, 3H), 4.16 (q, J = 8.5 Hz, 1H), 3.50-3.36 (m, 1H), 2.53 (p, J = 1.9 Hz, 4H), 2.35-1.68 (m, 13H), 1.63-1.47 (m, 1H), 0.48 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 488.0 (M + H)⁺. Example 8-bromo-5-(cyclohexylmethoxy)-N- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-84 (naphthalene-1-sulfonyl)-1,2,3,4- ppm 8.71-8.64 (m, 1H), 8.32-8.21 (m, 2H), tetrahydronaphthalene-1- 8.12 (dt, J = 8.0, 1.0 Hz, 1H), 7.82-7.74 (m, 1H), carboxamide 7.73-7.62 (m, 2H), 7.10 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 3.78 (dd, J = 6.3, 2.6 Hz, 1H), 3.72-3.61 (m, 2H), 2.53-2.48 (m, 1H), 2.34-2.20 (m, 1H), 1.92 (d, J = 14.0 Hz, 1H), 1.82-1.63 (m, 7H), 1.54-1.45 (m, 1H), 1.28-1.08 (m, 3H), 1.07-0.94 (m, 3H). MS (APCI+) m/z 555.9 (M + H)⁺. Example 8-bromo-5-[(3- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-85 methoxyphenyl)methoxy]-N- ppm 8.72-8.64 (m, 1H), 8.31-8.21 (m, 2H), (naphthalene-1-sulfonyl)-1,2,3,4- 8.15-8.08 (m, 1H), 7.81-7.61 (m, 3H), 7.28 (t, J = 7.9 Hz, tetrahydronaphthalene-1- 1H), 7.12 (d, J = 8.8 Hz, 1H), carboxamide 6.99-6.92 (m, 2H), 6.87 (dd, J = 8.2, 2.7 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 5.06-4.95 (m, 2H), 3.82-3.75 (m, 1H), 3.73 (s, 3H), 2.65-2.54 (m, 1H), 2.41-2.27 (m, 1H), 1.94 (d, J = 13.9 Hz, 1H), 1.83-1.70 (m, 1H), 1.52-1.47 (m, 1H), 1.10-1.02 (m, 1H). MS (APCI+) m/z 579.9 (M + H)⁺. Example 8-bromo-5-[(3- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-86 methoxyphenyl)methoxy]-N-[(3- ppm 8.40-8.26 (m, 3H), 8.13 (d, J = 8.1 Hz, 1H), methoxyphenyl)methyl]-N- 7.85-7.76 (m, 1H), 7.75-7.64 (m, 2H), (naphthalene-1-sulfonyl)-1,2,3,4- 7.38-7.33 (m, 1H), 7.32-7.16 (m, 3H), 7.12 (d, J = 8.7 Hz, tetrahydronaphthalene-1- 1H), 6.95-6.81 (m, 4H), 6.75 (d, J = 8.7 Hz, carboxamide 1H), 5.71-5.34 (m, 2H), 5.01-4.89 (m, 2H), 4.17-4.12 (m, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 2.46-2.29 (m, 1H), 2.18 (s, 1H), 1.56-1.51 (m, 2H), 1.03 (s, 1H), 0.57-0.09 (m, 1H). MS (APCI+) m/z 699.9 (M + H)⁺. Example ethyl ({4-bromo-5-[(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-87 sulfonyl)carbamoyl]-5,6,7,8- ppm 8.68 (dd, J = 8.6, 1.1 Hz, 1H), 8.33-8.17 (m, tetrahydronaphthalen-1- 2H), 8.16-8.09 (m, 1H), 7.82-7.75 (m, 1H) yl}oxy)acetate 7.73-7.62 (m, 2H), 7.10 (d, J = 8.7 Hz, 1H), 6.61 (d, J = 8.9 Hz, 1H), 4.71 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.79 (dd, J = 6.5, 2.6 Hz, 1H), 2.66-2.55 (m, 1H), 2.40-2.26 (m, 1H), 1.98-1.89 (m, 1H), 1.84-1.71 (m, 1H), 1.56-1.48 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H), 1.08-1.03 (m, 1H). MS (APCI+) m/z 545.7 (M + H)⁺. Example 8-bromo-5-(cyclopentyloxy)-N- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-88 (naphthalene-1-sulfonyl)-1,2,3,4- ppm 8.71-8.64 (m, 1H), 8.32-8.21 (m, 2H), tetrahydronaphthalene-1- 8.16-8.08 (m, 1H), 7.81-7.74 (m, 1H), carboxamide 7.73-7.62 (m, 2H), 7.09 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.71 (t, J = 5.7 Hz, 1H), 3.77 (dd, J = 6.5, 2.6 Hz, 1H), 2.53-2.42 (m, 1H), 2.29-2.15 (m, 1H), 1.92 (d, J = 13.5 Hz, 1H), 1.85-1.69 (m, 3H), 1.69-1.42 (m, 7H), 1.06-0.98 (m, 1H). MS (APCI+) m/z 527.9 (M + H)⁺. Example 5-(benzyloxy)-8-bromo-N- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-89 (naphthalene-1-sulfonyl)-1,2,3,4- ppm 8.71-8.64 (m, 1H), 8.26 (dd, J = 14.1, 7.6 Hz, tetrahydronaphthalene-1- 2H), 8.15-8.08 (m, 1H), 7.76 (t, J = 7.6 Hz, carboxamide 1H), 7.73-7.61 (m, 2H), 7.43-7.26 (m, 5H), 7.12 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 5.03 (d, J = 2.6 Hz, 2H), 3.82-3.75 (m, 1H), 2.64-2.54 (m, 1H), 2.40-2.26 (m, 1H), 1.98-1.90 (m, 1H), 1.80-1.70 (m, 1H), 1.55-1.46 (m, 1H), 1.09-1.04 (m, 1H). MS (APCI+) m/z 549.9 (M + H)⁺. Example N-benzyl-5-(benzyloxy)-8-bromo-N- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-90 (naphthalene-1-sulfonyl)-1,2,3,4- ppm 8.44-8.28 (m, 3H), 8.18-8.10 (m, 1H), tetrahydronaphthalene-1- 7.87-7.78 (m, 1H) 7.77-7.65 (m, 2H), carboxamide 7.65-7.60 (m, 2H), 7.48-7.43 (m, 2H), 7.42-7.25 (m, 6H), 7.17-7.06 (m, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.73-5.46 (m, 2H), 5.05-4.92 (m, 2H), 4.18-4.13 (m, 1H), 2.43-2.38 (m, 1H), 2.21-2.16 (m, 1H), 1.55-1.50 (m, 2H), 1.06-1.01 (m, 1H), 0.39-0.34 (m, 1H). MS (APCI+) m/z 639.9 (M + H)⁺. Example 8-bromo-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-91 sulfonyl)-5-[(oxetan-3-yl)oxy]- ppm 8.71 (d, J = 8.5 Hz, 1H), 8.37 8.20 (m, 2H), 1,2,3,4-tetrahydronaphthalene-1- 8.14 (d, J = 8.1 Hz, 1H), 7.90-7.75 (m, 1H), carboxamide 7.75-7.61 (m, 2H), 7.12 (d, J = 8.7 Hz, 1H), 6.33 (d, J = 8.7 Hz, 1H), 5.18 (q, J = 5.5 Hz, 1H), 4.97-4.87 (m, 2H), 4.53-4.42 (m, 2H), 2.67-2.59 (m, 2H), 2.44-2.33 (m, 1H), 2.05-1.92 (m, 1H), 1.89-1.74 (m, 1H), 1.64-1.42 (m, 1H), 1.28-0.94 (m, 1H). MS (APCI+) m/z 515.9 (M + H)⁺. Example 8-bromo-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-92 sulfonyl)-5-[(oxan-4-yl)oxy]-1,2,3,4- ppm 8.70 (d, J = 8.4 Hz, 1H), 8.32 7.87 (m, 3H), tetrahydronaphthalene-1- 7.81-7.42 (m, 3H), 7.09 (d, J = 8.8 Hz, 1H), carboxamide 6.73 (d, J = 8.9 Hz, 1H), 4.61-4.38 (m, 1H), 3.52-3.42 (m, 2H), 2.62-2.54 (m, 1H), 2.34-2.22 (m, 1H), 2.05-1.82 (m, 4H), 1.76-1.39 (m, 4H), 1.13 (d, J = 22.3 Hz, 1H). MS (APCI+) m/z 543.9 (M + H)⁺. Example 8-bromo-5-(2-hydroxy-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-93 methylpropoxy)-N-(naphthalene-1- ppm 8.73 8.65 (m, 1H), 8.32-8.22 (m, 2H), sulfonyl)-1,2,3,4- 8.12 (d, J = 8.2 Hz, 1H), 7.85-7.73 (m, 1H), tetrahydronaphthalene-1- 7.73-7.59 (m, 2H), 7.11 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 8.8 Hz, carboxamide 1H), 3.80-3.76 (m, 1H), 3.60 (d, J = 8.0 Hz, 2H), 2.65-2.57 (m, 1H), 2.39-2.20 (m, 1H), 1.99-1.88 (m, 1H), 1.85-1.68 (m, 1H), 1.53-1.41 (m, 1H), 1.17 (d, J = 2.0 Hz, 6H), 1.08-0.90 (m, 1H). MS (APCI+) m/z 531.9 (M + H)⁺. Example 6,8-dimethoxy-N-(naphthalene-1- ¹H NMR (501 MHz, DMSO) δ ppm 12.39 (s, 1H), II-94 sulfonyl)-1,2,3,4- 8.69 (dd, J = 1.0, 8.7 Hz, 1H), 8.28 (d, J = 8.3 Hz, tetrahydronaphthalene-1- 1H), 8.24 (dd, J = 1.3, 7.4 Hz, 1H), 8.14-8.12 (m, carboxamide 2H), 7.80 (ddd, J = 1.4, 6.9, 8.5 Hz, 1H), 7.71 (ddd, J = 1.1, 6.9, 8.1 Hz, 1H), 7.66 (dd, J = 7.4, 8.2 Hz, 1H), 6.16 (d, J = 2.4 Hz, 1H), 6.08 (d, J = 2.4 Hz, 1H), 3.63 (s, 3H), 3.58 (dd, J = 5.2, 6.9 Hz, 1H), 2.89 (s, 3H), 2.51-2.47 (m, 2H), 1.84-1.76 (m, 1H), 1.67-1.60 (m, 1H), 1.44-1.32 (m, 2H). LC/MS (APCI+) m/z 426 (M + H)⁺. Example 5-methoxy-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-95 sulfonyl)-8-[4- ppm 8.58-8.42 (m, 1H), 8.32 (d, J = 8.2 Hz, 1H), (trifluoromethoxy)phenyl]-1,2,3,4- 8.22 (dd, J = 7.5, 1.2 Hz, 1H), 8.20-8.02 (m, 1H), tetrahydronaphthalene-1- 7.82-7.59 (m, 3H), 7.04-6.76 (m, 6H), 3.75 (s, carboxamide 3H), 3.51 (dd, J = 5.6, 3.1 Hz, 1H), 2.50-2.23 (m, 2H), 1.82-1.66 (m, 1H), 1.66-1.50 (m, 1H), 1.44-1.28 (m, 1H), 0.98-0.78 (m, 1H). MS (APCI+) m/z 634.0 (M + H)⁺. Example 5-methoxy-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-96 sulfonyl)-8-[(E)-2-phenylethenyl]- ppm 8.66-8.57 (m, 1H), 8.28-8.14 (m, 2H), 1,2,3,4-tetrahydronaphthalene-1- 8.13-8.04 (m, 1H), 7.70-7.60 (m, 2H), 7.55 (dd, carboxamide J = 8.2, 7.4 Hz, 1H), 7.51-7.37 (m, 5H), 7.36-7.27 (m, 1H), 7.00 (d, J = 16.0 Hz, 1H), 6.91-6.81 (m, 2H), 4.10-4.03 (m, 1H), 3.74 (s, 3H), 2.54-2.43 (m, 1H), 2.34-2.21 (m, 1H), 1.83-1.65 (m, 2H), 1.38-1.33 (m, 1H), 1.04-0.96 (m, 1H). MS (APCI+) m/z 497.8 (M + H)⁺. Example 8-(2,2-difluoro-2H-1,3-benzodioxol- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-97 4-yl)-5-methoxy-N-(naphthalene-1- ppm 8.45-8.37 (m, 1H), 8.29 (d, J = 8.2 Hz, 1H), sulfonyl)-1,2,3,4- 8.18-8.10 (m, 2H), 7.77-7.68 (m, 2H), 7.64 (t, J = 7.8 Hz, tetrahydronaphthalene-1- 1H), 7.02 (d, J = 7.9 Hz, 1H), carboxamide 6.95-6.85 (m, 2H), 6.73-6.42 (m, 2H), 3.77 (s, 3H), 3.64 (s, 1H), 2.53-2.44 (m, 1H), 2.43-2.30 (m, 1H), 1.71-1.66 (m, 2H), 1.43-1.34 (m, 1H), 0.98-0.93 (m, 1H). MS (APCI+) m/z 552.0 (M + H)⁺. Example 8-(2-fluoro-4-methylphenyl)-5- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-98 methoxy-N-(naphthalene-1- ppm 8.60 (d, J = 8.4 Hz, 1H), 8.21-8.08 (m, 2H), sulfonyl)-1,2,3,4- 8.04 (d, J = 7.7 Hz, 1H), 7.66-7.54 (m, 3H), tetrahydronaphthalene-1- 6.83-6.74 (m, 3H), 6.68-6.63 (m, 1H), carboxamide 6.46-6.41 (m, 1H), 3.76 (s, 3H), 3.42 (s, 1H), 2.51-2.34 (m, 2H), 2.25 (s, 3H), 1.89 (d, J = 22.3 Hz, 1H), 1.65-1.47 (m, 1H), 1.46-1.05 (m, 2H). MS (APCI+) m/z 504.0 (M + H)⁺. Example 5-methoxy-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-99 sulfonyl)-8-(2-phenoxyphenyl)- ppm 8.79-8.58 (m, 1H), 8.16-7.84 (m, 3H), 1,2,3,4-tetrahydronaphthalene-1- 7.63-7.41 (m, 3H), 7.27-7.09 (m, 4H), 6.96 (t, J = 7.4 Hz, carboxamide 1H), 6.92-6.50 (m, 6H), 3.71 (s, 3H), 3.21-3.11 (m, 1H), 2.45-2.23 (m, 2H), 2.12-1.88 (m, 1H), 1.42-1.09 (m, 3H). MS (APCI+) m/z 564.0 (M + H)⁺. Example N-(3-bromo-2-methylbenzene-1- ¹H NMR (501 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-100 sulfonyl)-4-chloro-1-ethyl-2,3- ppm 7.98 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 7.8 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.33-7.27 (m, 1H), 7.27-7.20 (m, 2H), 2.86 (t, J = 7.3 Hz, 2H), 2.51 (s, 3H), 2.45 (dt, J = 13.1, 7.3 Hz, 1H), 2.14-1.99 (m, 2H), 1.76-1.62 (m, 1H), 0.68 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 457.9 (M + H)⁺. Example 4-chloro-1-ethyl-N-(3-fluoro-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-101 methylbenzene-1-sulfonyl)-2,3- ppm 7.84-7.76 (m, 1H), 7.56-7.42 (m, 2H), dihydro-1H-indene-1-carboxamide 7.35-7.20 (m, 3H), 2.86 (t, J = 7.3 Hz, 2H), 2.50-2.40 (m, 1H), 2.38 (d, J = 2.3 Hz, 3H), 2.13-1.98 (m, 2H), 1.81-1.67 (m, 1H), 0.68 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 396.1 (M + H)⁺. Example 4-chloro-1-ethyl-N-[2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-102 (methoxymethyl)benzene-1- ppm 7.95 (dd, J = 8.0, 1.3 Hz, 1H), 7.75-7.62 (m, sulfonyl]-2,3-dihydro-1H-indene-1- 2H), 7.56-7.47 (m, 1H), 7.36-7.20 (m, 3H), carboxamide 4.73 (s, 2H), 3.36 (s, 3H), 2.94-2.76 (m, 2H), 2.49-2.37 (m, 1H), 2.11-1.98 (m, 2H), 1.79-1.65 (m, 1H), 0.66 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z 408.1 (M + H)⁺. Example 4-chloro-N-(2,3-difluorobenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-103 sulfonyl)-1-ethyl-2,3-dihydro-1H- ppm 7.85-7.75 (m, 1H), 7.73-7.66 (m, 1H), indene-1-carboxamide 7.50-7.40 (m, 1H), 7.35-7.19 (m, 3H), 2.91-2.78 (m, 2H), 2.51-2.39 (m, 1H), 2.14-2.00 (m, 2H), 1.81-1.67 (m, 1H), 0.70 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 400.0 (M + H)⁺. Example 4-chloro-N-[2-(2,2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-104 difluoroethoxy)benzene-1-sulfonyl]- ppm 7.86 (dd, J = 7.9, 1.7 Hz, 1H), 7.72-7.62 (m, 1-ethyl-2,3-dihydro-1H-indene-1- 1H), 7.34-7.15 (m, 5H), 6.34 (tt, J = 54.6, 3.8 Hz, carboxamide 1H), 4.40 (dd, J = 54.8, 3.9 Hz, 2H), 2.86 (t, J = 7.3 Hz, 2H), 2.50-2.37 (m, 1H), 2.14-1.93 (m, 2H), 1.82-1.68 (m, 1H), 0.67 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 444.0 (M + H)⁺. Example 4-chloro-1-ethyl-N-(quinoxaline-5- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-105 sulfonyl)-2,3-dihydro-1H-indene-1- ppm 9.07 (d, J = 1.8 Hz, 1H), 8.99 (d, J = 1.8 Hz, carboxamide 1H), 8.51 (dd, J = 7.4, 1.4 Hz, 1H), 8.43 (dd, J = 8.5, 1.4 Hz, 1H), 8.05 (dd, J = 8.5, 7.4 Hz, 1H), 7.27-7.18 (m, 1H), 7.17-7.08 (m, 2H), 2.86-2.66 (m, 2H), 2.46-2.34 (m, 1H), 2.11-1.96 (m, 2H), 1.74-1.60 (m, 1H), 0.53 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 416.0 (M + H)⁺. Example 4-chloro-N-(3-chloro-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-106 fluorobenzene-1-sulfonyl)-1-ethyl- ppm 7.94 (ddd, J = 8.2, 6.8, 1.7 Hz, 1H), 2,3-dihydro-1H-indene-1- 7.86 (ddd, J = 8.1, 6.5, 1.7 Hz, 1H), 7.51-7.41 (m, carboxamide 1H), 7.35-7.19 (m, 3H), 2.95-2.78 (m, 2H), 2.51-2.39 (m, 1H), 2.15-2.01 (m, 2H), 1.81-1.67 (m, 1H), 0.69 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z 416.0 (M + H)⁺. Example 4-chloro-N-(2,3-dichlorobenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-107 sulfonyl)-1-ethyl-2,3-dihydro-1H- ppm 8.07 (dd, J = 8.1, 1.5 Hz, 1H), 7.96 (dd, J = 8.1, indene-1-carboxamide 1.5 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.33-7.19 (m, 3H), 2.95-2.82 (m, 2H), 2.52-2.40 (m, 1H), 2.16-1.99 (m, 2H), 1.84-1.70 (m, 1H), 0.70 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 433.9 (M + H)⁺. Example 4-chloro-1-ethyl-N-(1-methyl-1H- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-108 indole-3-sulfonyl)-2,3-dihydro-1H- ppm 8.07 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.57 (d, indene-1-carboxamide J = 8.2 Hz, 1H), 7.38-7.30 (m, 1H), 7.29-7.23 (m, 3H), 7.21-7.14 (m, 1H), 3.86 (s, 3H), 2.88-2.70 (m, 2H), 2.42-2.30 (m, 1H), 2.10-1.91 (m, 2H), 1.74-1.60 (m, 1H), 0.55 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 417.1 (M + H)⁺. Example 5-[2-(1,3-dioxan-2-yl)ethyl]-8- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-109 methoxy-N-(naphthalene-1- ppm 8.69 (d, J = 8.7 Hz, 1H), 8.33-8.21 (m, 2H), sulfonyl)-1,2,3,4- 8.18-8.10 (m, 1H), 7.87-7.78 (m, 1H), tetrahydronaphthalene-1- 7.77-7.63 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, carboxamide 1H), 4.46 (t, J = 5.1 Hz, 1H), 3.97 (ddd, J = 11.8, 5.0, 1.4 Hz, 2H), 3.72-3.60 (m, 3H), 2.88 (s, 3H), 2.52-2.34 (m, 4H), 1.93-1.74 (m, 2H), 1.70-1.52 (m, 3H), 1.51-1.27 (m, 3H). MS (APCI+) m/z 510.0 (M + H)⁺. Example 4-cyano-7-methoxy-N-(naphthalene- ¹H NMR (501 MHz, DMSO-d₆) δ ppm 12.64 (s, II-110 1-sulfonyl)-2,3-dihydro-1H-indene- 1H), 8.64 (dd, J = 8.7, 1.1 Hz, 1H), 8.31 (d, J = 8.3 Hz, 1-carboxamide 1H), 8.27 (dd, J = 7.4, 1.2 Hz, 1H), 8.15 (dt, J = 8.2, 0.9 Hz, 1H), 7.81 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.74-7.66 (m, 2H), 7.61 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 4.00 (dd, J = 9.2, 5.7 Hz, 1H), 3.17 (s, 3H), 2.91 (dt, J = 8.7, 6.1 Hz, 2H), 2.35 (dtd, J = 13.1, 8.8, 6.3 Hz, 1H), 1.86 (ddt, J = 12.7, 8.7, 6.3 Hz, 1H). MS (APCI+) m/z 407 (M + H)⁺. Example 5-cyano-8-methoxy-N-(naphthalene- ¹H NMR (501 MHz, DMSO) δ ppm 12.58 (s, 1H), II-111 1-sulfonyl)-1,2,3,4- 8.68 (dd, J = 1.0, 8.7 Hz, 1H), 8.30 (d, J = 8.2 Hz, tetrahydronaphthalene-1- 1H), 8.24 (dd, J = 1.2, 7.4 Hz, 1H), 8.14 (d, J = 8.0 Hz, carboxamide 1H), 7.82 (ddd, J = 1.4, 6.9, 8.5 Hz, 1H), 7.72 (ddd, J = 1.1, 6.9, 8.1 Hz, 1H), 7.67 (dd, J = 7.4, 8.2 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 3.69 (dd, J = 4.7, 6.7 Hz, 1H), 3.01 (s, 3H), 2.72-2.60 (m, 2H), 1.89-1.81 (m, 1H), 1.77-1.69 (m, 1H), 1.56-1.48 (m, 1H), 1.42-1.32 (m, 1H). LC/MS (ESI+) m/z 421 (M + H)⁺. Example 4-chloro-N-(3-cyclobutyl-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-112 methylbenzene-1-sulfonyl)-1-ethyl- ppm 7.80 (dd, J = 7.9, 1.3 Hz, 1H), 7.48 (d, J = 7.7 Hz, 2,3-dihydro-1H-indene-1- 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.28-7.15 (m, carboxamide 3H), 3.74-3.59 (m, 1H), 2.90-2.83 (m, 2H), 2.53-2.48 (m, 1H), 2.41-2.30 (m, 5H), 2.13-1.93 (m, 5H), 1.88-1.65 (m, 2H), 0.72 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z 432.0 (M + H)⁺. Example 4-chloro-1-ethyl-N-(isoquinoline-5- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-113 sulfonyl)-2,3-dihydro-1H-indene-1- ppm 9.39 (s, 1H), 8.62-8.46 (m, 1H), 8.42 (d, J = 6.1 Hz, carboxamide 1H), 8.40-8.27 (m, 2H), 7.80 (t, J = 7.8 Hz, 1H), 7.26-7.16 (m, 2H), 7.16-7.07 (m, 1H), 2.84-2.75 (m, 2H), 2.55-2.45 (m, 1H), 2.12-1.91 (m, 1H), 1.91-1.77 (m, 1H), 1.65-1.46 (m, 1H), 0.54 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 415.6 (M + H)⁺. Example 5-methoxy-N-(naphthalene-1- ¹H NMR (500 MHz, DMSO) δ ppm 12.78 (s, 1H), II-114 sulfonyl)bicyclo[4.2.0]octa-1,3,5- 8.61 (dd, J = 1.0, 8.6 Hz, 1H), 8.32-8.28 (m, 2H), triene-7-carboxamide 8.14 (d, J = 8.0 Hz, 1H), 7.79 (ddd, J = 1.4, 6.9, 8.5 Hz, 1H), 7.73-7.67 (m, 2H), 7.10-7.07 (m, 1H), 6.61-6.57 (m, 2H), 4.38 (dd, J = 2.5, 5.8 Hz, 1H), 3.32 (s, 3H), 3.29 (dd, J = 5.8, 14.0 Hz, 1H), 2.76 (dd, J = 2.5, 14.0 Hz, 1H). LC/MS (ESI+) m/z 368 (M + H)⁺. Example 8-methoxy-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.44 (s, II-115 sulfonyl)-1,2,3,4- 1H), 8.70 (d, J = 8.6 Hz, 1H), 8.28 (d, J = 8.2 Hz, tetrahydronaphthalene-1- 1H), 8.24 (dd, J = 7.4, 1.2 Hz, 1H), 8.15-8.12 (m, carboxamide 1H), 7.81 (ddd, J = 8.6, 6.8, 1.4 Hz, 1H), 7.71 (ddd, J = 8.2, 6.8, 1.1 Hz, 1H), 7.66 (dd, J = 8.2, 7.4 Hz, 1H), 7.00 (dd, J = 8.0, 7.6 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 3.69-3.65 (m, 1H), 2.91 (s, 3H), 2.56-2.51 (m, 2H), 1.88-1.79 (m, 1H), 1.71-1.62 (m, 1H), 1.47-1.33 (m, 2H). MS (ESI+) m/z 396 (M + H)⁺. Example 4-bromo-7-methoxy-N-(quinoline-8- ¹H NMR (501 MHz, DMSO-d₆) δ ppm 12.44 (s, II-116 sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 9.16-9.02 (m, 1H), 8.57 (d, J = 8.3 Hz, 1H), carboxamide 8.40 (dd, J = 7.4, 1.4 Hz, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.84-7.68 (m, 2H), 7.28 (d, J = 8.6 Hz, 1H), 6.62 (d, J = 8.7 Hz, 1H), 4.12 (bs, 1H), 3.30 (s, 3H), 2.70 (ddd, J = 16.2, 9.1, 5.2 Hz, 1H), 2.60 (td, J = 16.2, 14.8, 6.7 Hz, 1H), 2.32-2.20 (m, 1H), 1.84-1.74 (m, 1H). MS (APCI+) m/z 461 (M + H)⁺. Example 4-bromo-N-(8-fluoroquinoline-5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.71 (s, II-117 sulfonyl)-7-methoxy-2,3-dihydro- 1H), 9.15 (dd, J = 4.2, 1.5 Hz, 1H), 9.06 (d, J = 8.9 Hz, 1H-indene-1-carboxamide 1H), 8.36 (dd, J = 8.4, 4.9 Hz, 1H), 7.95 (dd, J = 8.9, 4.2 Hz, 1H), 7.81 (dd, J = 10.0, 8.4 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 4.02 (dd, J = 9.2, 5.7 Hz, 1H), 3.12 (s, 3H), 2.77 (t, J = 7.5 Hz, 2H), 2.30 (ddt, J = 13.1, 8.9, 7.3 Hz, 1H), 1.90-1.76 (m, 1H). MS (APCI+) m/z 479 (M + H)⁺. Example 7-ethyl-5-methoxy-N-(naphthalene- ¹H NMR (501 MHz, DMSO-d₆) δ ppm 12.18 (s, II-118 1-sulfonyl)bicyclo[4.2.0]octa-1,3,5- 1H), 8.62 (d, J = 8.6 Hz, 1H), 8.31-8.26 (m, 2H), triene-7-carboxamide 8.11 (d, J = 8.3 Hz, 1H), 7.75 (ddd, J = 1.3, 6.7, 8.5 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.1 Hz, 1H), 7.13 (dd, J = 7.2, 8.5 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 7.2 Hz, 1H), 3.65 (s, 3H), 3.07 (d, J = 14.3 Hz, 1H), 2.98 (d, J = 14.3 Hz, 1H), 2.05 (dq, J = 7.4, 14.7 Hz, 1H), 1.79 (dq, J = 7.3, 14.6 Hz, 1H), 0.58 (t, J = 7.4 Hz, 3H). LC/MS (ESI+) m/z 396 (M + H)⁺. Example 8-methoxy-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-119 sulfonyl)-5-[3- ppm 8.71 (dd, J = 8.6, 1.1 Hz, 1H), 8.33-8.24 (m, (trifluoromethoxy)phenyl]-1,2,3,4- 2H), 8.19-8.11 (m, 1H), 7.88-7.80 (m, 1H), tetrahydronaphthalene-1- 7.77-7.66 (m, 2H), 7.52 (t, J = 8.0 Hz, 1H), carboxamide 7.33-7.27 (m, 1H), 7.26-7.22 (m, 1H), 7.15-7.11 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 3.78-3.74 (m, 1H), 2.92 (s, 3H), 2.49-2.26 (m, 2H), 1.98-1.80 (m, 1H), 1.76-1.61 (m, 1H), 1.52-1.24 (m, 2H). MS (APCI+) m/z 556.0 (M + H)⁺. Example 8-methoxy-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-120 sulfonyl)-5-[(E)-2-phenylethenyl]- ppm 8.70 (d, J = 8.7 Hz, 1H), 8.27 (dd, J = 14.9, 1,2,3,4-tetrahydronaphthalene-1- 7.8 Hz, 2H), 8.14 (d, J = 8.2 Hz, 1H), 7.83 (t, J = 7.7 Hz, carboxamide 1H), 7.77-7.59 (m, 3H), 7.58-7.51 (m, 2H), 7.47-7.18 (m, 5H), 6.87 (d, J = 16.1 Hz, 1H), 6.62 (d, J = 8.6 Hz, 1H), 3.72-3.68 (m, 1H), 2.98 (s, 3H), 2.74-2.57 (m, 2H), 1.76 (d, J = 33.3 Hz, 2H), 1.59-1.28 (m, 2H). MS (APCI+) m/z 497.8 (M + H)⁺. Example 5-(3,6-dihydro-2H-pyran-4-yl)-8- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-121 methoxy-N-(naphthalene-1- ppm 8.70 (d, J = 8.7 Hz, 1H), 8.33-8.22 (m, 2H), sulfonyl)-1,2,3,4- 8.14 (dt, J = 8.2, 0.9 Hz, 1H), 7.88-7.79 (m, 1H), tetrahydronaphthalene-1- 7.78-7.63 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), carboxamide 6.52 (d, J = 8.5 Hz, 1H), 5.49-5.43 (m, 1H), 4.11 (q, J = 2.8 Hz, 2H), 3.74 (t, J = 10.7 Hz, 2H), 3.70-3.65 (m, 1H), 2.87 (s, 3H), 2.47 (t, J = 6.2 Hz, 2H), 2.22-2.04 (m, 2H), 1.91-1.79 (m, 1H), 1.63 (d, J = 13.6 Hz, 1H), 1.50-1.28 (m, 2H). MS (APCI+) m/z 478.0 (M + H)⁺. Example 5-methoxy-8-(6-methylpyridin-3- ¹H NMR (501 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-122 yl)-N-(naphthalene-1-sulfonyl)- ppm 8.55-8.48 (m, 1H), 8.31 (d, J = 8.3 Hz, 1H), 1,2,3,4-tetrahydronaphthalene-1- 8.23-8.14 (m, 2H), 8.08 (d, J = 2.4 Hz, 1H), carboxamide 7.80-7.71 (m, 2H), 7.68 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.88-6.79 (m, 2H), 6.50 (d, J = 8.0 Hz, 1H), 3.75 (s, 3H), 3.51 (s, 1H), 2.51-2.24 (m, 5H), 1.81-1.66 (m, 1H), 1.66-1.52 (m, 2H), 1.41-1.31 (m, 1H), 0.96-0.79 (m, 1H). MS (APCI+) m/z 487.0 (M + H)⁺. Example 4-bromo-N-(2-ethoxyquinoline-5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.62 (s, II-123 sulfonyl)-7-methoxy-2,3-dihydro- 1H), 8.90 (dd, J = 9.3, 0.7 Hz, 1H), 8.12 (dd, J = 7.5, 1H-indene-1-carboxamide 1.2 Hz, 1H), 8.09 (dt, J = 8.4, 1.1 Hz, 1H), 7.83 (dd, J = 8.4, 7.5 Hz, 1H), 7.31 (dd, J = 9.3, 1.6 Hz, 2H), 6.62 (d, J = 8.7 Hz, 1H), 4.58-4.46 (m, 2H), 4.04 (dd, J = 9.2, 5.6 Hz, 1H), 3.22 (s, 3H), 2.78 (t, J = 7.5 Hz, 2H), 2.33-2.25 (m, 1H), 1.89-1.76 (m, 1H), 1.41 (t, J = 7.1 Hz, 3H). MS (APCI+) m/z 505 (M + H)⁺. Example 8-methoxy-N-(naphthalene-1- ¹H NMR (501 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-124 sulfonyl)-5-(pyrrolidin-1-yl)-1,2,3,4- ppm 8.75-8.62 (m, 1H), 8.31 (d, J = 8.3 Hz, 1H), tetrahydronaphthalene-1- 8.25 (dd, J = 7.3, 1.2 Hz, 1H), 8.15 (d, J = 8.2 Hz, carboxamide 1H), 7.84 (ddd, J = 8.5, 6.9, 1.3 Hz, 1H), 7.74 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.68 (dd, J = 8.2, 7.4 Hz, 1H), 7.35 (d, J = 8.9 Hz, 1H), 6.71 (d, J = 9.2 Hz, 1H), 3.51 (s, 3H), 2.95 (s, 3H), 2.66-2.55 (m, 4H), 2.20-2.00 (m, 4H), 1.95-1.78 (m, 1H), 1.78-1.65 (m, 1H), 1.61-1.48 (m, 1H), 1.46-1.31 (m, 1H). MS (APCI+) m/z 465.1 (M + H)⁺. Example 4-chloro-1-ethyl-N-[2-methyl-3- ¹H NMR (501 MHz, pyridine-d₅) δ ppm 8.39 (dd, II-125 (piperidin-1-yl)benzene-1-sulfonyl]- J = 8.0, 1.3 Hz, 1H), 7.36-7.32 (m, 2H), 7.22 (d, 2,3-dihydro-1H-indene-1- J = 1.1 Hz, 1H), 7.19 (d, J = 1.0 Hz, 1H), 7.13 (t, J = 7.7 Hz, carboxamide 1H), 2.84 (s, 3H), 2.82-2.78 (m, 2H), 2.77-2.71 (m, 1H), 2.69-2.59 (m, 4H), 2.12-2.00 (m, 2H), 1.98-1.90 (m, 1H), 1.58 (p, J = 5.7 Hz, 4H), 1.47-1.37 (m, 2H), 0.79 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z 461.3 (M + H)⁺. Example 4-chloro-N-[3-(3,3-difluoroazetidin- ¹H NMR (501 MHz, pyridine-d₅) δ ppm 8.26 (d, J = 7.8 Hz, II-126 1-yl)-2-methylbenzene-1-sulfonyl]- 1H), 7.42-7.36 (m, 1H), 7.26 (t, J = 8.0 Hz, 1-ethyl-2,3-dihydro-1H-indene-1- 1H), 7.19 (d, J = 1.1 Hz, 1H), 7.14 (t, J = 7.6 Hz, carboxamide 1H), 6.78 (dd, J = 8.1, 1.2 Hz, 1H), 4.24 (td, J = 12.0, 3.2 Hz, 4H), 2.87-2.74 (m, 3H), 2.67 (s, 3H), 2.13-2.04 (m, 2H), 1.95 (dq, J = 14.6, 7.4 Hz, 1H), 0.81 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 469.2 (M + H)⁺. Example 4-chloro-N-[3-(3,3- ¹H NMR (501 MHz, Pyridine-d₅) δ ppm 8.54 (dd, II-127 difluoropyrrolidin-1-yl)-2- J = 7.9, 1.3 Hz, 1H), 7.37-7.31 (m, 2H), 7.20 (d, methylbenzene-1-sulfonyl]-1-ethyl- J = 1.1 Hz, 1H), 7.18 (d, J = 1.1 Hz, 1H), 7.13 (td, 2,3-dihydro-1H-indene-1- J = 7.8, 3.7 Hz, 2H), 3.47-3.39 (m, 1H), 3.14 (t, J = 6.9 Hz, carboxamide 1H), 2.91 (s, 2H), 2.88-2.80 (m, 3H), 2.79 (s, 2H), 2.79-2.74 (m, 1H), 2.39 (tt, J = 14.5, 6.9 Hz, 1H), 2.13-2.02 (m, 3H), 1.99-1.86 (m, 1H), 0.80 (td, J = 7.4, 4.4 Hz, 4H). MS (APCI+) m/z 483.2 (M + H)⁺. Example 5-chloro-8-hydroxy-N-(naphthalene- ¹H NMR (400 MHz, CDCl₃) δ ppm 9.04 (bs, 1H), II-128 1-sulfonyl)-1,2,3,4- 8.51 (dd, J = 7.4, 1.2 Hz, 1H), 8.40-8.36 (m, 1H), tetrahydronaphthalene-1- 8.12 (d, J = 8.2 Hz, 1H), 7.98-7.94 (m, 1H), carboxamide 7.64-7.56 (m, 3H), 7.16-7.11 (m, 1H), 6.52 (d, J = 8.5 Hz, 1H), 3.75-3.71 (m, 1H), 2.72-2.62 (m, 1H), 2.57-2.46 (m, 1H), 2.03? (m, 1H), 1.69-1.55 (m, 3H). MS (ESI+) m/z 416 (M + H)⁺. Example 5-methoxy-N-(naphthalene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-129 sulfonyl)-8-[6- ppm 8.53-8.42 (m, 2H), 8.35-8.27 (m, 1H), (trifluoromethyl)pyridin-3-yl]- 8.22-8.10 (m, 2H), 7.78-7.59 (m, 3H), 1,2,3,4-tetrahydronaphthalene-1- 7.45-7.28 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.5 Hz, carboxamide 1H), 3.77 (s, 3H), 3.65-3.60 (m, 1H), 2.50-2.27 (m, 2H), 1.71-1.52 (m, 2H), 1.38-1.31 (m, 1H), 1.03-0.75 (m, 1H). MS (APCI+) m/z 541.0 (M + H)⁺. Example 8-(3,6-dihydro-2H-pyran-4-yl)-5- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-130 methoxy-N-(naphthalene-1- ppm 8.67 (d, J = 8.6 Hz, 1H), 8.41-8.03 (m, 2H), sulfonyl)-1,2,3,4- 7.90-7.51 (m, 4H), 6.88-6.65 (m, 2H), 5.14 (s, tetrahydronaphthalene-1- 1H), 3.83 (d, J = 23.4 Hz, 4H), 3.68-3.42 (m, carboxamide 4H), 2.46-2.20 (m, 2H), 2.10-1.82 (m, 2H), 1.70-1.55 (m, 2H), 1.40-1.26 (m, 1H), 1.01-0.81 (m, 1H). MS (APCI+) m/z 478.0 (M + H)⁺. Example 8-(6-cyclopropylpyridin-3-yl)-5- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ II-131 methoxy-N-(naphthalene-1- ppm 8.50-8.43 (m, 1H), 8.34-8.27 (m, 1H), sulfonyl)-1,2,3,4- 8.22 (d, J = 2.1 Hz, 1H), 8.19-8.10 (m, 2H), tetrahydronaphthalene-1- 7.80-7.70 (m, 2H), 7.67 (dd, J = 8.2, 7.5 Hz, 1H), carboxamide 7.54 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 3.76 (s, 3H), 3.64 (t, J = 5.3 Hz, 1H), 2.49-2.30 (m, 2H), 2.29-2.18 (m, 1H), 1.71-1.58 (m, 1H), 1.53-1.43 (m, 1H), 1.37-1.31 (m, 1H), 1.30-1.22 (m, 2H), 1.16-1.03 (m, 2H), 0.96 (s, 1H). MS (APCI+) m/z 513.0 (M + H)⁺. Example 4-bromo-7-methoxy-N-[2-(propan-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.66 (s, II-132 yl)quinoline-5-sulfonyl]-2,3- 1H), 8.95 (dd, J = 9.0, 0.8 Hz, 1H), 8.29 (d, J = 8.4 Hz, dihydro-1H-indene-1-carboxamide 1H), 8.25 (dd, J = 7.5, 1.2 Hz, 1H), 7.88 (dd, J = 8.4, 7.5 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 6.57 (d, J = 8.7 Hz, 1H), 4.03 (dd, J = 9.2, 5.8 Hz, 1H), 3.29 (dt, J = 13.8, 7.2 Hz, 1H), 3.05 (s, 3H), 2.78 (t, J = 7.5 Hz, 2H), 2.31 (ddt, J = 13.1, 9.1, 7.4 Hz, 1H), 1.87 (dtd, J = 13.4, 8.1, 6.3 Hz, 1H), 1.36 (dd, J = 6.9, 1.6 Hz, 6H). MS (APCI+) m/z 503 (M + H)⁺. Example 4-bromo-7-methoxy-N-(5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.56 (s, II-133 methoxynaphthalene-1-sulfonyl)- 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.27 (dd, J = 7.4, 1.3 Hz, 2,3-dihydro-1H-indene-1- 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.71 (dd, J = 8.7, carboxamide 7.8 Hz, 1H), 7.65 (dd, J = 8.5, 7.4 Hz, 1H), 7.29 (dd, J = 8.7, 0.7 Hz, 1H), 7.18 (dd, J = 7.9, 0.7 Hz, 1H), 6.60 (d, J = 8.7 Hz, 1H), 4.05 (dd, J = 9.2, 5.6 Hz, 1H), 4.02 (s, 3H), 3.18 (s, 3H), 2.74 (ddd, J = 9.3, 6.6, 3.2 Hz, 2H), 2.27 (dtd, J = 13.1, 8.8, 6.6 Hz, 1H), 1.80 (dddd, J = 13.2, 8.4, 6.6, 5.6 Hz, 1H). MS (APCI+) m/z 490 (M + H)⁺. Example methyl 7-methoxy-1-[(naphthalene- ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm II-134 1-sulfonyl)carbamoyl]-2,3-dihydro- 12.59 (s, 1H), 8.66 (dd, J = 8.7, 1.1 Hz, 1H), 1H-indene-4-carboxylate 8.30 (d, J = 8.2 Hz, 1H), 8.26 (dd, J = 7.4, 1.3 Hz, 1H), 8.17-8.10 (m, 1H), 7.84-7.78 (m, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.74-7.71 (m, 1H), 7.68 (dd, J = 8.2, 7.4 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 3.95 (dd, J = 9.4, 5.6 Hz, 1H), 3.74 (s, 3H), 3.16 (s, 3H), 3.06 (t, J = 7.6 Hz, 2H), 2.35-2.21 (m, 1H), 1.80 (td, J = 13.1, 7.2 Hz, 1H). MS (APCI+) m/z 440 (M + H)⁺. Example methyl 5-[(4-bromo-7-methoxy-2,3- ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm II-135 dihydro-1H-indene-1- 12.68 (s, 1H), 9.13-8.91 (m, 2H), 8.30 (ddd, J = 40.1, carbonyl)sulfamoyl]naphthalene-1- 7.4, 1.1 Hz, 2H), 7.86 (ddd, J = 25.6, 8.8, 7.4 Hz, carboxylate 2H), 7.29 (d, J = 8.7 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 4.04 (dd, J = 9.2, 5.6 Hz, 1H), 3.98 (s, 3H), 3.12 (s, 3H), 2.75 (t, J = 7.5 Hz, 2H), 2.28 (ddt, J = 15.0, 9.3, 7.4 Hz, 1H), 1.82 (dtd, J = 13.0, 7.4, 5.6 Hz, 1H). MS(ESI−) m/z 515.8 (M − H)⁻. Example 5-chloro-8-[2-(morpholin-4- ¹H NMR (501 MHz, CD₂Cl₂) δ ppm II-136 yl)ethoxy]-N-(naphthalene-1- 8.57-8.54 (m, 1/H), 8.38 (dd, J = 7.4, 1.2 Hz, 1H), 8.18 (d, J = 8.3 Hz, sulfonyl)-1,2,3,4- 1H), 8.02-8.00 (m, 1H), 7.73 (ddd, J = 8.5, tetrahydronaphthalene-1- 6.9, 1.4 Hz, 1H), 7.66 (ddd, J = 8.1, 6.9, 1.2 Hz, carboxamide 1H), 7.63-7.59 (m, 1H), 7.25 (d, J = 8.7 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 4.38-4.32 (m, 1H), 4.10-4.05 (m, 4H), 3.94-3.89 (m, 1H), 3.83-3.78 (m, 1H), 3.78-3.74 (m, 1H), 3.69-3.64 (m, 1H), 3.60-3.54 (m, 1H), 3.30-3.25 (m, 1H), 3.15-3.08 (m, 1H), 3.00-2.93 (m, 1H), 2.66-2.49 (m, 2H), 1.77-1.68 (m, 1H), 1.49-1.39 (m, 3H). MS (ESI) m/z 529 (M + H)⁺. Example 4-chloro-1-methyl-N- III-3 (phenylmethanesulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-chloro-N-(1,3,5-trimethyl-1H- III-4 pyrazole-4-sulfonyl)-2,3-dihydro- 1H-indene-1-carboxamide Example 4-chloro-N-(2- III-5 methoxyethanesulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-chloro-N-(propane-1-sulfonyl)- III-6 2,3-dihydro-1H-indene-1- carboxamide Example 8-methoxy-N-(2-methylbenzene-1- MS (APCI+) m/z 360.1 (M + H)⁺. III-7 sulfonyl)-1,2,3,4- tetrahydronaphthalene-2- carboxamide Example 5-methoxy-N-(2-methylbenzene-1- MS (APCI+) m/z 346.1 (M + H)⁺. III-9 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example N-(2-methylbenzene-1-sulfonyl)- MS (APCI+) m/z 330.2 (M + H)⁺. III-10 1,2,3,4-tetrahydronaphthalene-2- carboxamide Example 4-methoxy-N-(1,3,5-trimethyl-1H- MS (ESI+) m/z 364 (M + H)⁺. III-11 pyrazole-4-sulfonyl)-2,3-dihydro- 1H-indene-1-carboxamide Example 4-methoxy-N-(2-methoxybenzene-1- MS (ESI+) m/z 362 (M + H)⁺. III-12 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example 4-methoxy-N-(5-methylpyridine-2- MS (ESI+) m/z 347 (M + H)⁺. III-13 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example 4-methoxy-N-(oxane-4-sulfonyl)- MS (ESI+) m/z 340 (M + H)⁺. III-14 2,3-dihydro-1H-indene-1- carboxamide Example 4-methoxy-N-(3-methoxypropane-1- MS (ESI+) m/z 328 (M + H)⁺. III-15 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example 4-methoxy-N-(2- MS (ESI+) m/z 314 (M + H)⁺. III-16 methoxyethanesulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-methoxy-N-(propane-1-sulfonyl)- III-17 2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-N-(2-methoxybenzene-1- III-18 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-N-(5-methylpyridine-2- III-19 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example N-(4-hydroxybenzene-1-sulfonyl)-4- MS (APCI+) m/z 347.9 (M + H)⁺. III-20 methoxy-2,3-dihydro-1H-indene-1- carboxamide Example 4-methoxy-N- MS (APCI+) m/z 345.9 (M + H)⁺. III-21 (phenylmethanesulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example N-(6-hydroxynaphthalene-2- MS (APCI+) m/z 398.0 (M + H)⁺. III-22 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example 4-methoxy-N-(4-methylbenzene-1- MS (APCI+) m/z 345.9 (M + H)⁺. III-23 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example N-(5-acetamido-1,3,4-thiadiazole-2- MS (APCI+) m/z 397.0 (M + H)⁺. III-24 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example 4-methoxy-N-[5-methyl-2-(propan- MS (APCI+) m/z 388.0 (M + H)⁺. III-25 2-yl)benzene-1-sulfonyl]-2,3- dihydro-1H-indene-1-carboxamide Example N-[4-(methanesulfonyl)benzene-1- ¹H NMR (400 MHz, DMSO-d₆: D₂O = 9:1 (v/v)) δ III-26 sulfonyl]-4-methoxy-2,3-dihydro- ppm 8.17 (s, 4H), 7.14 (t, J = 7.9 Hz, 1H), 1H-indene-1-carboxamide 6.89-6.67 (m, 2H), 4.01 (dd, J = 8.3, 5.8 Hz, 1H), 3.74 (s, 3H), 3.29 (s, 3H), 2.88-2.64 (m, 2H), 2.25-2.06 (m, 2H). Example 4-methoxy-N-(3-nitrobenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ III-27 sulfonyl)-2,3-dihydro-1H-indene-1- ppm 8.64-8.58 (m, 1H), 8.53 (ddd, J = 8.2, 2.3, carboxamide 1.0 Hz, 1H), 8.34 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 7.93 (t, J = 8.1 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 6.79 (dd, J = 7.9, 5.4 Hz, 2H), 4.00 (dd, J = 8.2, 5.8 Hz, 1H), 3.74 (s, 3H), 2.86-2.64 (m, 2H), 2.25-2.04 (m, 2H). Example N-(4-chloro-3-nitrobenzene-1- ¹H NMR (400 MHz, DMSO-d₆: D₂O = 9:1 (v/v)) δ III-28 sulfonyl)-4-methoxy-2,3-dihydro- ppm 8.49 (d, J = 2.2 Hz, 1H), 8.17 (dd, J = 8.5, 2.3 Hz, 1H-indene-1-carboxamide 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.8 Hz, 2H), 3.98 (t, J = 7.0 Hz, 1H), 3.75 (s, 3H), 2.87-2.64 (m, 2H), 2.22-2.08 (m, 2H). Example N-(6-chloro-1,1-dioxo-1,2-dihydro- MS (APCI+) m/z 369.9 (M + H)⁺. III-29 1λ⁶,2,4-benzothiadiazine-7- sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example 4-methoxy-N-(2-methyl-5- ¹H NMR (400 MHz, DMSO-d₆: D₂O = 9:1 (v/v)) δ III-30 nitrobenzene-1-sulfonyl)-2,3- ppm 8.64 (d, J = 2.5 Hz, 1H), 8.39 (dd, J = 8.4, 2.5 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.15 (t, J = 7.9 Hz, 1H), 6.82 (t, J = 7.6 Hz, 2H), 4.03 (dd, J = 8.5, 5.4 Hz, 1H), 3.74 (s, 3H), 2.91-2.63 (m, 5H), 2.27-2.11 (m, 1H), 2.15-2.03 (m, 1H). Example N-(4-acetamido-2-methylbenzene-1- MS (APCI+) m/z 403.0 (M + H)⁺. III-31 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-(4-chlorobenzene-1-sulfonyl)-4- ¹H NMR (400 MHz, DMSO-d₆: D₂O = 9:1 (v/v)) δ III-32 methoxy-2,3-dihydro-1H-indene-1- ppm 7.96-7.88 (m, 2H), 7.73-7.65 (m, 2H), carboxamide 7.13 (t, J = 7.8 Hz, 1H), 6.79 (dd, J = 14.2, 7.9 Hz, 2H), 4.01-3.93 (m, 1H), 3.75 (s, 3H), 2.87-2.64 (m, 2H), 2.24-2.04 (m, 2H). Example N-(4-chloro-2-nitrobenzene-1- ¹H NMR (400 MHz, DMSO-d₆: D₂O = 9:1 (v/v)) δ III-33 sulfonyl)-4-methoxy-2,3-dihydro- ppm 8.23 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H-indene-1-carboxamide 1H), 7.94 (dd, J = 8.7, 2.1 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.04 (t, J = 7.1 Hz, 1H), 3.75 (s, 3H), 2.89-2.66 (m, 2H), 2.29-2.08 (m, 2H). Example 4-methoxy-N-(naphthalene-2- MS (APCI+) m/z 382.0 (M + H)⁺. III-34 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example N-(3-chlorobenzene-1-sulfonyl)-4- ¹H NMR (400 MHz, DMSO-d₆: D₂O = 9:1 (v/v)) δ III-35 methoxy-2,3-dihydro-1H-indene-1- ppm 7.92-7.84 (m, 2H), 7.81-7.74 (m, 1H), carboxamide 7.66 (t, J = 8.2 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 6.79 (dd, J = 12.2, 7.9 Hz, 2H), 4.03-3.94 (m, 1H), 3.75 (s, 3H), 2.87-2.65 (m, 2H), 2.25-2.05 (m, 2H). Example 4-methoxy-N-[4-(3- MS (APCI+) m/z 431.0 (M + H)⁺. III-36 oxobutanamido)benzene-1- sulfonyl]-2,3-dihydro-1H-indene-1- carboxamide Example N-(2,4-dichlorobenzene-1-sulfonyl)- MS (APCI+) m/z 400.2 (M + H)⁺. III-37 4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example N-(4-amino-2-chloro-5- MS (APCI+) m/z 395.1 (M + H)⁺. III-38 methylbenzene-1-sulfonyl)-4- methoxy-2,3-dihydro-1H-indene-1- carboxamide Example N-(2-chloro-5-methylbenzene-1- MS (APCI+) m/z 380.0 (M + H)⁺. III-39 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-(2-chloro-5-nitrobenzene-1- MS (APCI+) m/z 411.0 (M + H)⁺. III-40 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-(4-acetamidobenzene-1-sulfonyl)- MS (APCI+) m/z 389.0 (M + H)⁺. III-41 4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example N-(4-acetamido-2-chlorobenzene-1- MS (APCI+) m/z 423. (M + H)⁺. III-42 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-(4-butanamidobenzene-1- MS (APCI+) m/z 417.0 (M + H)⁺. III-43 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-(5-chloro-1,3-dimethyl-1H- MS (APCI+) m/z 384.0 (M + H)⁺. III-44 pyrazole-4-sulfonyl)-4-methoxy-2,3- dihydro-1H-indene-1-carboxamide Example N-(2,4-dihydroxy-6- ¹H NMR (400 MHz, DMSO-d₆: D₂O = 9:1 (v/v)) δ III-45 methylpyrimidine-5-sulfonyl)-4- ppm 7.14 (t, J = 7.9 Hz, 1H), 6.83 (dd, J = 12.6, methoxy-2,3-dihydro-1H-indene-1- 7.8 Hz, 2H), 4.04 (t, J = 7.2 Hz, 1H), 3.76 (s, 3H), carboxamide 2.93-2.67 (m, 2H), 2.46 (s, 3H), 2.25-2.08 (m, 2H). Example N-(4-cyanobenzene-1-sulfonyl)-4- ¹H NMR (400 MHz, DMSO-d₆: D₂O = 9:1 (v/v)) δ III-46 methoxy-2,3-dihydro-1H-indene-1- ppm 8.08 (s, 4H), 7.14 (t, J = 7.9 Hz, 1H), carboxamide 6.79 (dd, J = 14.1, 7.8 Hz, 2H), 3.99 (dd, J = 8.3, 5.9 Hz, 1H), 3.75 (s, 3H), 2.86-2.64 (m, 2H), 2.24-2.03 (m, 2H). Example 4-methoxy-N-(2-oxo-2H-1- ¹H NMR (400 MHz, DMSO-d₆: D₂O = 9:1 (v/v)) δ III-47 benzopyran-6-sulfonyl)-2,3-dihydro- ppm 8.29 (d, J = 2.3 Hz, 1H), 8.18 (d, J = 9.7 Hz, 1H-indene-1-carboxamide 1H), 8.08 (dd, J = 8.8, 2.4 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.80 (t, J = 8.0 Hz, 2H), 6.61 (d, J = 9.6 Hz, 1H), 3.96 (t, J = 7.1 Hz, 1H), 3.73 (s, 3H), 2.86-2.63 (m, 2H), 2.19-2.07 (m, 2H). Example ethyl 4-[(4-methoxy-2,3-dihydro- MS (APCI+) m/z 404.1 (M + H)⁺. III-48 1H-indene-1- carbonyl)sulfamoyl]benzoate Example N-(2,4-dimethyl-3-nitrobenzene-1- MS (APCI+) m/z 405.0 (M + H)⁺. III-49 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-{2-chloro-5-[(2,6- MS (APCI+) m/z 528.9 (M + H)⁺. III-50 dimethylphenyl)carbamoyl]-4- hydroxybenzene-1-sulfonyl}-4- methoxy-2,3-dihydro-1H-indene-1- carboxamide Example N-[1-(2-chloroethyl)-3,5-dimethyl- MS (APCI+) m/z 412.0 (M + H)⁺. III-51 1H-pyrazole-4-sulfonyl]-4-methoxy- 2,3-dihydro-1H-indene-1- carboxamide Example N-[3-({[(2S)-1-ethylpyrrolidin-2- MS (APCI+) m/z 516.0 (M + H)⁺. III-52 yl]methyl}carbamoyl)-4- methoxybenzene-1-sulfonyl]-4- methoxy-2,3-dihydro-1H-indene-1- carboxamide Example N-(6-ethoxy-1,3-benzothiazole-2- MS (APCI+) m/z 433.0 (M + H)⁺. III-53 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-(4-hexanoylbenzene-1-sulfonyl)- MS (APCI+) m/z 430.3 (M + H)⁺. III-54 4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example N-[4-(4-{2-[(1S)-3,4-dihydro-1H-2- MS (APCI+) m/z 576.1 (M + H)⁺. III-55 benzopyran-1-yl]ethyl}piperazin-1- yl)benzene-1-sulfonyl]-4-methoxy- 2,3-dihydro-1H-indene-1- carboxamide Example propan-2-yl 2-[(4-methoxy-2,3- MS (APCI+) m/z 418.0 (M + H)⁺. III-56 dihydro-1H-indene-1- carbonyl)sulfamoyl]benzoate Example N-{4-[(3-hydroxy-3- MS (APCI+) m/z 478.0 (M + H)⁺. III-57 methylbutyl)amino]-3-nitrobenzene- 1-sulfonyl}-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-[2-chloro-5-(1,3-dimethyl-2,6- MS (APCI+) m/z 543.8 (M + H)⁺. III-58 dioxo-2,3,6,7-tetrahydro-1H-purin- 8-yl)benzene-1-sulfonyl]-4- methoxy-2,3-dihydro-1H-indene-1- carboxamide Example N-{7-[(4-chlorophenyl)methyl]-1,3- MS (APCI+) m/z 557.8 (M + H)⁺. III-59 dimethyl-2,6-dioxo-2,3,6,7- tetrahydro-1H-purine-8-sulfonyl}-4- methoxy-2,3-dihydro-1H-indene-1- carboxamide Example N-(9-benzyl-1,3-dimethyl-2,6-dioxo- MS (APCI+) m/z 524.0 (M + H)⁺. III-60 2,3,6,9-tetrahydro-1H-purine-8- sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-{4- MS (APCI+) m/z 389.0 (M + H)⁺. III-61 [(dimethylamino)methyl]benzene-1- sulfonyl}-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-(2-cyano-3-fluorobenzene-1- MS (APCI+) m/z 374.3 (M + H)⁺. III-62 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-(4-hydroxy-3-nitrobenzene-1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ III-63 sulfonyl)-4-methoxy-2,3-dihydro- ppm 8.36 (d, J = 2.4 Hz, 1H), 8.01 (dd, J = 8.9, 2.4 Hz, 1H-indene-1-carboxamide 1H), 7.27 (d, J = 8.9 Hz, 1H), 7.12 (t, J = 7.9 Hz, 1H), 6.79 (dd, J = 14.2, 7.9 Hz, 2H), 3.98 (dd, J = 8.2, 5.9 Hz, 1H), 3.75 (s, 3H), 2.87-2.65 (m, 2H), 2.25-2.05 (m, 2H). Example N-(3-cyanobenzene-1-sulfonyl)-4- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ III-64 methoxy-2,3-dihydro-1H-indene-1- ppm 8.29 (t, J = 1.8 Hz, 1H), 8.26-8.19 (m, 1H), carboxamide 8.19-8.12 (m, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 6.80 (dd, J = 9.9, 7.9 Hz, 2H), 4.00 (dd, J = 8.2, 5.9 Hz, 1H), 3.75 (s, 3H), 2.87-2.65 (m, 2H), 2.25-2.04 (m, 2H). Example N-(5-bromopyridine-3-sulfonyl)-4- MS (APCI+) m/z 410.8 (M + H)⁺. III-65 methoxy-2,3-dihydro-1H-indene-1- carboxamide Example N-(6-hydroxypyridine-3-sulfonyl)-4- MS (APCI+) m/z 348.9 (M + H)⁺. III-66 methoxy-2,3-dihydro-1H-indene-1- carboxamide Example N-(4-cyano-1,3-dimethyl-1H- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) δ III-67 pyrazole-5-sulfonyl)-4-methoxy-2,3- ppm 8.06 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 2.1 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.66 (dd, J = 8.6, 2.1 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 4.06 (dd, J = 8.5, 5.6 Hz, 1H), 3.75 (s, 3H), 2.87-2.66 (m, 2H), 2.29-2.04 (m, 2H). Example tert-butyl 5-[(4-methoxy-2,3- MS (APCI+) m/z 450.0 (M + H)⁺. III-68 dihydro-1H-indene-1- carbonyl)sulfamoyl]-1,3-dimethyl- 1H-pyrazole-4-carboxylate Example N-[4-(hydroxymethyl)-1,3-dimethyl- MS (APCI+) m/z 380.0 (M + H)⁺. III-69 1H-pyrazole-5-sulfonyl]-4-methoxy- 2,3-dihydro-1H-indene-1- carboxamide Example N-(3-chloro-2-fluorobenzene-1- III-70 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-(2,6-difluorobenzene-1-sulfonyl)- III-71 4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example 4,5-dimethoxy-N-(2-methylbenzene- III-72 1-sulfonyl)-2,3-dihydro-1H-indene- 1-carboxamide Example N-(5-chloro-2-fluorobenzene-1- III-73 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-(2,5-difluorobenzene-1-sulfonyl)- III-74 4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example N-(2-chloro-5-fluorobenzene-1- III-75 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-(2,6-dichlorobenzene-1-sulfonyl)- III-76 4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example N-(2,4-difluorobenzene-1-sulfonyl)- III-77 4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example 4-methoxy-N-[1-(2-methoxyethyl)- III-78 1H-pyrazole-4-sulfonyl]-2,3- dihydro-1H-indene-1-carboxamide Example N-(3,5-dimethyl-1,2-oxazole-4- III-79 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example N-(2,4-dimethyl-1,3-thiazole-5- III-80 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example 4-methoxy-N-(pyridine-3-sulfonyl)- III-81 2,3-dihydro-1H-indene-1- carboxamide Example 2-[(4-methoxy-2,3-dihydro-1H- III-82 indene-1-carbonyl)sulfamoyl]-N,N- dimethylpyridine-3-carboxamide Example N-(2-cyanopyridine-3-sulfonyl)-4- III-83 methoxy-2,3-dihydro-1H-indene-1- carboxamide Example 4-methoxy-N-(pyridine-2-sulfonyl)- III-84 2,3-dihydro-1H-indene-1- carboxamide Example 4-(6-methoxypyridin-3-yl)-N-(2- III-85 methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- III-86 [6-(piperidin-1-yl)pyridin-3-yl]-2,3- dihydro-1H-indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- III-87 [6-(4-methylpiperazin-1-yl)pyridin- 3-yl]-2,3-dihydro-1H-indene-1- carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- III-88 (2-methylpyridin-3-yl)-2,3-dihydro- 1H-indene-1-carboxamide Example 4-(6-fluoropyridin-3-yl)-N-(2- III-89 methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-[6-(dimethylamino)pyridin-3-yl]- III-90 N-(2-methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-(5-fluoropyridin-3-yl)-N-(2- III-91 methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- III-92 (5-methylpyridin-3-yl)-2,3-dihydro- 1H-indene-1-carboxamide Example 4-(2-fluoropyridin-4-yl)-N-(2- III-93 methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-(3-fluoropyridin-4-yl)-N-(2- III-94 methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- III-95 (3-methylpyridin-4-yl)-2,3-dihydro- 1H-indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- III-96 (2-methylpyridin-4-yl)-2,3-dihydro- 1H-indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- III-97 (1H-pyrazol-4-yl)-2,3-dihydro-1H- indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- III-98 (1H-pyrazol-5-yl)-2,3-dihydro-1H- indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- III-99 (thiophen-3-yl)-2,3-dihydro-1H- indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- ¹H NMR 400 MHz (CDCl₃) δ ppm 8.26 (1H, d); III-100 [6-(morpholin-4-yl)pyridin-3-yl]- 8.16 (1H, d); 8.02 (1H, s); 7.52 (1H, t); 7.39 (1H, 2,3-dihydro-1H-indene-1- t); 7.27-7.33 (4H, m); 6.79 (1H, d); 6.73 (1H, s br); carboxamide 4.09 (1H, t); 3.87 (4H, m); 3.68 (4H, m); 3.07-3.14 (1H, m); 2.88-2.96 (1H, m); 2.63 (3H, s); 2.38-2.45 (1H, m); 2.28-2.31 (1H, m). MS (ESI+) m/z 478 (M + H)⁺. Example N-(2-methylbenzene-1-sulfonyl)-4- MS (ESI+) m/z 396 (M + H)⁺. III-101 (3-methyl-1H-pyrazol-4-yl)-2,3- dihydro-1H-indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- MS (ESI+) m/z 396 (M + H)⁺. III-102 (1-methyl-1H-pyrazol-4-yl)-2,3- dihydro-1H-indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- MS (ESI+) m/z 396 (M + H)⁺. III-103 (5-methylfuran-2-yl)-2,3-dihydro- 1H-indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- MS (ESI+) m/z 396 (M + H)⁺. III-104 (2-methylfuran-3-yl)-2,3-dihydro- 1H-indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- MS (ESI+) m/z 424 (M + H)⁺. III-105 (1,3,5-trimethyl-1H-pyrazol-4-yl)- 2,3-dihydro-1H-indene-1- carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- MS (ESI+) m/z 396 (M + H)⁺. III-106 (1-methyl-1H-pyrazol-5-yl)-2,3- dihydro-1H-indene-1-carboxamide Example (1R)-N-(2-aminopyridine-3- MS (APCI+) m/z 362 (M + H)⁺. III-107 sulfonyl)-5-methoxy-1,2,3,4- tetrahydronaphthalene-1- carboxamide Example N-(6-aminopyridine-2-sulfonyl)-1,5- MS (ESI+) m/z 346 (M + H)⁺. III-108 dimethyl-2,3-dihydro-1H-indene-1- carboxamide Example (1R)-N-(6-aminopyridine-2- MS (APCI+) m/z 362 (M + H)⁺. III-109 sulfonyl)-5-methoxy-1,2,3,4- tetrahydronaphthalene-1- carboxamide Example N-(6-aminopyridine-2-sulfonyl)-8- MS (APCI+) m/z 366 (M + H)⁺. III-110 chloro-1,2,3,4- tetrahydronaphthalene-1- carboxamide Example 4-chloro-N-(naphthalene-1- MS (ESI+) m/z 483 (M + H)⁺. III-111 sulfonyl)-1-[2-(pyrrolidin-1- yl)ethyl]-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-1-{2-[(2- MS (ESI+) m/z 501 (M + H)⁺. III-112 methoxyethyl)(methyl)amino]ethyl}- N-(naphthalene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-chloro-N-(2,4-dichlorobenzene-1- MS (APCI+) m/z 431.9 (M + H)⁺. III-113 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example 4-chloro-N-(2,4-dimethylbenzene-1- MS (APCI+) m/z 392.1 (M + H)⁺. III-114 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example 4-chloro-N-(2,6-difluorobenzene-1- MS (APCI+) m/z 400.0 (M + H)⁺. III-115 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example 4-chloro-N-(2,5-dichlorobenzene-1- MS (APCI+) m/z 431.9 (M + H)⁺. III-116 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example 4-chloro-N-(3-chlorobenzene-1- MS (APCI+) m/z 398.0 (M + H)⁺. III-117 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example 4-chloro-N-(2-chloro-5- MS (APCI+) m/z 412.0 (M + H)⁺. III-118 methylbenzene-1-sulfonyl)-1-ethyl- 2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-1-ethyl-N-[4- MS (APCI+) m/z 447.9 (M + H)⁺. III-119 (trifluoromethoxy)benzene-1- sulfonyl]-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-N-(2-cyanobenzene-1- MS (APCI+) m/z 389.0 (M + H)⁺. III-120 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example 4-chloro-N-(2,6-dimethoxybenzene- MS (APCI+) m/z 424.0 (M + H)⁺. III-121 1-sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example 4-chloro-1-ethyl-N-[2- MS (APCI+) m/z 432.0 (M + H)⁺. III-122 (trifluoromethyl)benzene-1- sulfonyl]-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-N-(2,3-dihydro-1,4- MS (APCI+) m/z 422.0 (M + H)⁺. III-123 benzodioxine-6-sulfonyl)-1-ethyl- 2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-N-(2-chloro-6- MS (APCI+) m/z 412.0 (M + H)⁺. III-124 methylbenzene-1-sulfonyl)-1-ethyl- 2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-N-(4-chlorobenzene-1- MS (APCI+) m/z 398.0 (M + H)⁺. III-125 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example 4-chloro-1-ethyl-N-[2-methyl-6- MS (APCI+) m/z 445.9 (M + H)⁺. III-126 (trifluoromethyl)benzene-1- sulfonyl]-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-N-(2-cyano-3- MS (APCI+) m/z 407.0 (M + H)⁺. III-127 fluorobenzene-1-sulfonyl)-1-ethyl- 2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-1-ethyl-N-(1- MS (APCI+) m/z 342.1 (M + H)⁺. III-128 methylcyclopropane-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example N-([1,1′-biphenyl]-4-sulfonyl)-4- MS (APCI+) m/z 440.0 (M + H)⁺. III-129 chloro-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example 4-chloro-N-{4- MS (APCI+) m/z 421.0 (M + H)⁺. III-130 [(dimethylamino)methyl]benzene-1- sulfonyl}-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example 4-chloro-N-(5-chloro-1,3-dimethyl- MS (APCI+) m/z 416.0 (M + H)⁺. III-131 1H-pyrazole-4-sulfonyl)-1-ethyl-2,3- dihydro-1H-indene-1-carboxamide Example 4-chloro-N-(2-chloropyridine-3- MS (APCI+) m/z 399.0 (M + H)⁺. III-132 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example 4-chloro-1-ethyl-N-(quinoline-6- MS (APCI+) m/z 415.0 (M + H)⁺. III-133 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-N-(6-chloroimidazo[2,1- MS (APCI+) m/z 443.9 (M + H)⁺. III-134 b][1,3]thiazole-5-sulfonyl)-1-ethyl- 2,3-dihydro-1H-indene-1- carboxamide Example 2-[(4-chloro-1-ethyl-2,3-dihydro- MS (APCI+) m/z 436.0 (M + H)⁺. III-135 1H-indene-1-carbonyl)sulfamoyl]- N,N-dimethylpyridine-3- carboxamide Example 4-chloro-N-(cyclohexanesulfonyl)-1- MS (APCI+) m/z 370.1 (M + H)⁺. III-136 ethyl-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-1-ethyl-N-{4-[4-(propan-2- MS (APCI+) m/z 491.0 (M + H)⁺. III-137 yl)piperazin-1-yl]pyridine-3- sulfonyl}-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-1-ethyl-N-{2-[2-(piperidin- MS (APCI+) m/z 491.0 (M + H)⁺. III-138 1-yl)ethoxy]benzene-1-sulfonyl}- 2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-1-ethyl-N-(4- MS (APCI+) m/z 378.1 (M + H)⁺. III-139 methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-chloro-1-ethyl-N- MS (APCI+) m/z 378.1 (M + H)⁺. III-140 (phenylmethanesulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-chloro-1-ethyl-N-(2-methyl-1,3- MS (APCI+) m/z 446.9 (M + H)⁺. III-141 dioxo-2,3-dihydro-1H-isoindole-4- sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-1-ethyl-N-(4- MS (APCI+) m/z 394.1 (M + H)⁺. III-142 methoxybenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-chloro-1-ethyl-N-(4- MS (APCI+) m/z 456.0 (M + H)⁺. III-143 phenoxybenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-chloro-N-(3-cyanobenzene-1- MS (APCI+) m/z 389.0 (M + H)⁺. III-144 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example 4-chloro-1-ethyl-N-(1H-pyrazole-3- MS (APCI+) m/z 354.1 (M + H)⁺. III-145 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example 3-{4-chloro-1-[(naphthalene-1- MS (APCI+) m/z 386.0 (M + H)⁺. III-146 sulfonyl)carbamoyl]-2,3-dihydro- 1H-inden-1-yl}propanoic acid Example 4-chloro-N-(naphthalene-1- MS (APCI+) m/z 476.9 (M + H)⁺. III-147 sulfonyl)-1-[(pyridin-2-yl)methyl]- 2,3-dihydro-1H-indene-1- carboxamide Example 5-methoxy-N-(naphthalene-1- MS (APCI+) m/z 556.0 (M + H)⁺. III-148 sulfonyl)-8-[3- (trifluoromethoxy)phenyl]-1,2,3,4- tetrahydronaphthalene-1- carboxamide Example methyl 2-chloro-6-[(4-chloro-1- MS (APCI+) m/z 455.8 (M + H)⁺. III-149 ethyl-2,3-dihydro-1H-indene-1- carbonyl)sulfamoyl]benzoate Example 4-chloro-1-ethyl-N-methyl-N- MS (ESI+) m/z 428 (M + H)⁺. III-150 (naphthalene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-chloro-1-(methoxymethyl)-N- MS (ESI+) m/z 430 (M + H)⁺. III-151 (naphthalene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-bromo-7-hydroxy-N-(naphthalene- MS (APCI+) m/z 446.0 (M + H)⁺. III-152 1-sulfonyl)-2,3-dihydro-1H-indene- 1-carboxamide Example 5-methoxy-8-(morpholin-4-yl)-N- MS (APCI+) m/z 481.0 (M + H)⁺. III-153 (naphthalene-1-sulfonyl)-1,2,3,4- tetrahydronaphthalene-1- carboxamide Example 5-methoxy-N-(naphthalene-1- MS (APCI+) m/z 540.0 (M + H)⁺. III-154 sulfonyl)-8-[4- (trifluoromethyl)phenyl]-1,2,3,4- tetrahydronaphthalene-1- carboxamide Example 4-chloro-1-(cyanomethyl)-N- MS (ESI+) m/z 442 (M + NH₄)⁺. III-155 (naphthalene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example 4-chloro-N-(3-chloro-2- MS (APCI+) m/z 412.0 (M + H)⁺. III-156 methylbenzene-1-sulfonyl)-1-ethyl- 2,3-dihydro-1H-indene-1- carboxamide Example 8-chloro-1-cyano-N-(naphthalene-1- MS (ESI+) m/z 442 (M + NH₄)⁺. III-157 sulfonyl)-1,2,3,4- tetrahydronaphthalene-1- carboxamide Example 4-bromo-7-methoxy-N-(2- MS (APCI+) m/z 441 (M + H)⁺. III-158 methoxypyridine-3-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example N-(2-aminopyridine-3-sulfonyl)-4- MS (APCI+) m/z 426 (M + H)⁺. III-159 bromo-7-methoxy-2,3-dihydro-1H- indene-1-carboxamide Example N-(6-aminopyridine-2-sulfonyl)-4- MS (APCI+) m/z 426 (M + H)⁺. III-160 bromo-7-methoxy-2,3-dihydro-1H- indene-1-carboxamide Example 4-bromo-N-(4-ethoxynaphthalene-1- MS (APCI+) m/z 504 (M + H)⁺. III-161 sulfonyl)-7-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example 4-bromo-7-methoxy-N-(4- MS (APCI+) m/z 490 (M + H)⁺. III-162 methoxynaphthalene-1-sulfonyl)- 2,3-dihydro-1H-indene-1- carboxamide Example 4-bromo-7-methoxy-N- MS (APCI+) 452 m/z (M + H)⁺. III-163 ([1,2,4]triazolo[4,3-a]pyridine-8- sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example 8-methoxy-N-(naphthalene-1- MS (APCI+) m/z 474.0 (M + H)⁺. III-164 sulfonyl)-5-(pyrimidin-5-yl)-1,2,3,4- tetrahydronaphthalene-1- carboxamide Example 5-(6-cyclopropylpyridin-3-yl)-8- MS (APCI+) m/z 513.0 (M + H)⁺. III-165 methoxy-N-(naphthalene-1- sulfonyl)-1,2,3,4- tetrahydronaphthalene-1- carboxamide Example 8-methoxy-N-(naphthalene-1- MS (APCI+) m/z 473.0 (M + H)⁺. III-166 sulfonyl)-5-(pyridin-4-yl)-1,2,3,4- tetrahydronaphthalene-1- carboxamide Example 8-methoxy-5-(6-methylpyridin-3- MS (APCI+) m/z 487.0 (M + H)⁺. III-167 yl)-N-(naphthalene-1-sulfonyl)- 1,2,3,4-tetrahydronaphthalene-1- carboxamide Example 7-methoxy-4-(pyrimidin-5-yl)-N- MS (APCI+) m/z 461.0 (M + H)⁺. III-168 (quinoline-5-sulfonyl)-2,3-dihydro- 1H-indene-1-carboxamide Example 4-(3,6-dihydro-2H-pyran-4-yl)-7- MS (APCI+) m/z 465.0 (M + H)⁺. III-169 methoxy-N-(quinoline-5-sulfonyl)- 2,3-dihydro-1H-indene-1- carboxamide Example 8-methoxy-5-(4-methylphenyl)-N- MS (APCI+) m/z 486.0 (M + H)⁺. III-170 (naphthalene-1-sulfonyl)-1,2,3,4- tetrahydronaphthalene-1- carboxamide Example 8-methoxy-N-(naphthalene-1- MS (APCI+) m/z 541.0 (M + H)⁺. III-171 sulfonyl)-5-[6- (trifluoromethyl)pyridin-3-yl]- 1,2,3,4-tetrahydronaphthalene-1- carboxamide Example 4-chloro-1-ethyl-N-[2-methyl-3- MS (APCI+) m/z 463.2 (M + H)⁺. III-172 (morpholin-4-yl)benzene-1- sulfonyl]-2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-1-ethyl-N-{3-[(2- MS (APCI+) m/z 465.2 (M + H)⁺. III-173 methoxyethyl)(methyl)amino]-2- methylbenzene-1-sulfonyl}-2,3- dihydro-1H-indene-1-carboxamide Example 5-methoxy-N-(naphthalene-1- MS (APCI+) m/z 465.1 (M + H)⁺. III-174 sulfonyl)-8-(pyrrolidin-1-yl)-1,2,3,4- tetrahydronaphthalene-1- carboxamide Example 2,3-dimethoxy-N-(2- MS (APCI+) m/z 362.1 (M + H)⁺. III-175 methylbenzene-1- sulfonyl)bicyclo[4.2.0]octa-1,3,5- triene-7-carboxamide Example N-(2-methylbenzene-1- MS (APCI+) m/z 302.1 (M + H)⁺. III-176 sulfonyl)bicyclo[4.2.0]octa-1,3,5- triene-7-carboxamide Example 2,3-dimethoxy-N-(naphthalene-1- MS (APCI+) m/z 398.0 (M + H)⁺. III-177 sulfonyl)bicyclo[4.2.0]octa-1,3,5- triene-7-carboxamide Example 2-methoxy-N-(naphthalene-1- ¹H NMR (400 MHz, Chloroform-d) δ ppm III-178 sulfonyl)-6,7-dihydro-5H- 8.52 (ddd, J = 8.4, 4.0, 1.2 Hz, 2H), 8.14 (d, J = 8.2 Hz, cyclopenta[b]pyridine-5- 1H), 7.98 (dd, J = 7.9, 1.5 Hz, 1H), 7.73-7.57 (m, carboxamide 3H), 7.13 (dd, J = 8.5, 0.8 Hz, 1H), 6.35 (d, J = 8.3 Hz, 1H), 3.86 (s, 3H), 3.83-3.79 (m, 1H), 3.00-2.88 (m, 1H), 2.81 (ddd, J = 16.7, 9.0, 6.6 Hz, 1H), 2.40-2.28 (m, 1H), 2.11-2.01 (m, 1H), 1.37-1.20 (m, 1H). MS (ESI+) m/z 383.2 (M + H)⁺. Example 2-chloro-6-[(4-chloro-1-ethyl-2,3- MS (APCI+) m/z 441.9 (M + H)⁺. III-179 dihydro-1H-indene-1- carbonyl)sulfamoyl]benzoic acid Example 1-methoxy-N-(naphthalene-1- ¹H NMR (400 MHz, Chloroform-d) δ ppm III-180 sulfonyl)-6,7-dihydro-5H- 10.13 (s, 1H), 8.77 (dd, J = 6.9, 1.2 Hz, 1H), 8.35 (dd, J = 7.5, cyclopenta[c]pyridine-7- 1.2 Hz, 1H), 8.26 (s, 1H), 7.38 (d, J = 8.6 Hz, carboxamide 1H), 7.20 (t, J = 7.1 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 4.19-4.13 (m, 1H), 4.11 (s, 3H), 2.95-2.72 (m, 2H), 2.58 (ddt, J = 11.8, 7.5, 2.2 Hz, 1H), 2.11 (dq, J = 12.5, 9.0 Hz, 1H). MS (APCI+) 452 m/z (M + H)⁺. Example 5-[(4-bromo-7-methoxy-2,3- ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm III-181 dihydro-1H-indene-1- 12.67 (s, 1H), 9.14 (d, J = 8.7 Hz, 1H), 8.89 (d, J = 8.7 Hz, carbonyl)sulfamoyl]naphthalene-1- 1H), 8.34 (d, J = 7.2 Hz, 1H), 8.26 (d, J = 7.0 Hz, carboxylic acid 1H), 7.94-7.79 (m, 2H), 7.29 (d, J = 8.7 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 4.04 (dd, J = 9.2, 5.6 Hz, 1H), 3.13 (s, 3H), 2.75 (t, J = 7.5 Hz, 2H), 2.28 (tt, J = 13.3, 4.7 Hz, 1H), 1.89-1.75 (m, 1H). MS (ESI−) m/z 515.8 (M − H)⁻. MS (ESI+) m/z = 504 (M + H)⁺. Example 7-methoxy-N-(naphthalene-1- ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm III-182 sulfonyl)-2,3-dihydro-1H-indene-1- 12.52 (s, 1H), 8.67 (dd, J = 8.6, 1.0 Hz, 1H), carboxamide 8.30 (d, J = 8.3 Hz, 1H), 8.26 (dd, J = 7.4, 1.3 Hz, 1H), 8.17-8.11 (m, 1H), 7.80 (ddd, J = 8.5, 6.8, 1.4 Hz, 1H), 7.74-7.70 (m, 1H), 7.68 (dd, J = 8.2, 7.4 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.73 (d, J = 7.4 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 3.94 (dd, J = 9.0, 5.8 Hz, 1H), 3.10 (s, 3H), 2.78-2.71 (m, 2H), 2.29-2.16 (m, 1H), 1.85-1.72 (m, 1H). MS (APCI+) m/z 382 (M + H)⁺. Example 7-methoxy-1-[(naphthalene-1- ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm III-183 sulfonyl)carbamoyl]-2,3-dihydro- 12.57 (s, 1H), 12.42 (s, 1H), 8.66 (dd, J = 8.7, 1.1 Hz, 1H-indene-4-carboxylic acid 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.26 (dd, J = 7.4, 1.2 Hz, 1H), 8.14 (dd, J = 8.3, 1.3 Hz, 1H), 7.80 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.73-7.61 (m, 2H), 6.70 (d, J = 8.6 Hz, 1H), 3.94 (dd, J = 9.4, 5.6 Hz, 1H), 3.16 (s, 3H), 3.06 (t, J = 7.5 Hz, 2H), 2.25 (ddt, J = 13.1, 9.4, 7.5 Hz, 1H), 1.80 (dtd, J = 13.0, 7.4, 5.5 Hz, 1H). MS (APCI+) m/z 426 (M + H)⁺. Example methyl 7-methoxy-3-[(naphthalene- MS (APCI+) m/z 440.0 (M + H)⁺. III-184 1-sulfonyl)carbamoyl]-2,3-dihydro- 1H-indene-4-carboxylate Example 4-(hydroxymethyl)-7-methoxy-N- ¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ ppm III-185 (naphthalene-1-sulfonyl)-2,3- 12.50 (s, 1H), 8.68 (d, J = 8.7 Hz, 1H), 8.30 (d, J = 8.2 Hz, dihydro-1H-indene-1-carboxamide 1H), 8.27 (d, J = 7.5 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.83-7.78 (m, 1H), 7.75-7.65 (m, 2H), 7.07 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H), 4.86 (s, 1H), 4.41-4.17 (m, 2H), 3.95 (dd, J = 9.1, 5.8 Hz, 1H), 3.10 (d, J = 1.1 Hz, 3H), 2.73 (q, J = 6.6 Hz, 2H), 2.23 (dq, J = 14.9, 8.0 Hz, 1H), 1.79 (dq, J = 14.0, 6.8 Hz, 1H). MS (APCI+) m/z 412 (M + H)⁺. Example 7-methoxy-N⁴-methyl-N¹- ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm III-186 (naphthalene-1-sulfonyl)-2,3- 12.55 (s, 1H), 8.67 (dd, J = 8.7, 1.0 Hz, 1H), dihydro-1H-indene-1,4- 8.30 (d, J = 8.2 Hz, 1H), 8.26 (dd, J = 7.4, 1.2 Hz, 1H), dicarboxamide 8.18-8.13 (m, 1H), 7.93 (q, J = 4.5 Hz, 1H), 7.80 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.72 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.68 (dd, J = 8.2, 7.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 3.93 (dd, J = 9.2, 5.7 Hz, 1H), 3.13 (s, 3H), 2.97 (t, J = 7.5 Hz, 2H), 2.67 (d, J = 4.6 Hz, 3H), 2.29-2.15 (m, 1H), 1.77 (ddd, J = 13.3, 7.7, 5.8 Hz, 1H). MS (APCI+) m/z 439 (M + H)⁺. Example 7-methoxy-N⁴,N⁴-dimethyl-N¹- ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm III-187 (naphthalene-1-sulfonyl)-2,3- 12.58 (s, 1H), 8.69-8.65 (m, 1H), 8.31 (d, J = 8.3 Hz, dihydro-1H-indene-1,4- 1H), 8.27 (dd, J = 7.4, 1.3 Hz, 1H), dicarboxamide 8.17-8.13 (m, 1H), 7.81 (ddd, J = 8.5, 6.8, 1.4 Hz, 1H), 7.75-7.71 (m, 1H), 7.69 (dd, J = 8.2, 7.5 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 3.97 (dd, J = 9.0, 5.8 Hz, 1H), 3.11 (s, 3H), 2.89 (s, 3H), 2.76 (s, 3H), 2.68 (t, J = 7.4 Hz, 2H), 2.32-2.19 (m, 1H), 1.85-1.72 (m, 1H). MS (APCI+) m/z 453 (M + H)⁺. Example 7-methoxy-N-(naphthalene-1- ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm III-188 sulfonyl)-4-[(pyrrolidin-1- 12.60 (s, 1H), 9.49 (s, 1H), 8.71-8.62 (m, 1H), yl)methyl]-2,3-dihydro-1H-indene- 8.31 (d, J = 8.3 Hz, 1H), 8.26 (dd, J = 7.4, 1.3 Hz, 1-carboxamide 1H), 8.15 (dd, J = 8.3, 1.3 Hz, 1H), 7.81 (ddd, J = 8.6, 6.9, 1.4 Hz, 1H), 7.76-7.64 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 4.17 (d, J = 5.3 Hz, 2H), 3.99 (dd, J = 9.0, 5.7 Hz, 1H), 3.33 (m, 2H), 3.16 (s, 3H), 3.03 (m, 2H), 2.87 (t, J = 7.5 Hz, 2H), 2.27 (dq, J = 12.9, 7.8 Hz, 1H), 1.99 (d, J = 7.8 Hz, 2H), 1.90-1.75 (m, 3H). MS (APCI+) m/z 465 (M + H)⁺.

Determination of Biological Activity

Cell Surface Expression-Horse Radish Peroxidase (CSE-HRP) Assay

A cellular assay for measuring the F508delCFTR cell surface expression after correction with test compounds either without or with a co-corrector (2 μM of 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid), was developed in human lung derived epithelial cell line (CFBE41o-) (Veit G et al, (2012) Mol Biol Cell. 23(21): 4188-4202). The development was achieved by expressing the F508delCFTR mutation along with a horseradish peroxidase (HRP) in the fourth exofacial loop, and then measuring the HRP activity using luminescence readout from these cells, CFBE41o-F508delCFTR-HRP, that were incubated overnight with the test corrector compounds, either without or with the co-corrector. For this primary assay, the CFBE41o-F508delCFTR-HRP cells were plated in 384-well plates (Greiner Bio-one; Cat 781080) at 4,000 cells/well along with 0.5 μg/mL doxycycline to induce the F508delCFTR-HRP expression and further incubated at 37° C., 5% CO₂ for 72 hours. The test compounds were then added either without or with a co-corrector at the required concentrations and further incubated for 18-24 hours at 33° C. The highest concentration tested was 20 μM with an 8-point concentration response curve using a 3-fold dilution in both the test compound without or with the co-corrector. Three replicate plates were run to determine one EC₅₀. All plates contained negative controls (dimethyl sulfoxide, DMSO) and positive control (2 μM of 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) as well as on-plate concentration response of the positive control. Post incubation, the plates were washed 5× times with Dulbecco's phosphate buffered saline (DPBS), followed by the addition of the HRP substrate, luminol (50 μL), and measuring the HRP activity using luminescence readout on EnVision® Multilabel Plate Reader (Perkin Elmer; product number 2104-0010). The raw counts from the experiment were analyzed using Accelrys® Assay Explorer v3.3.

Z′ greater than 0.5 was used as passing quality control criteria for the plates.

The Z′ is defined as:

1−[3*SD_(Positive Control)+3*SD_(Negative Control)/Absolute (Mean_(Positive Control)−Mean_(Negative Control))]

wherein “SD” is standard deviation.

The % activity measured at each of the 8 test concentrations of the test compound added either without or with a co-corrector (2 μM of 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) was normalized to the on-plate positive control using the following formulae:

% activity (Test compound without co-corrector)=[(test compound without co-corrector response−DMSO response)/(positive control response−DMSO response)]*100%

activity (Test compound with co-corrector)=[(test compound with co-corrector response−DMSO response)/(positive control response−DMSO response)]*100

The maximum % activity achieved for the test compound either without or with a co-corrector at any tested concentration is presented in Table 1 along with the respective EC₅₀'s calculated using the following general sigmoidal curve with variable Hill slope equation (described as Model 42 in the Accelrys® Assay Explorer v3.3 software):

y=(a−d)/(1+(x/c)̂b)+d

General sigmoidal curve with concentration, response, top, bottom, EC₅₀ and Hill slope. This model describes a sigmoidal curve with an adjustable baseline, a. The equation can be used to fit curves where response is either increasing or decreasing with respect to the independent variable, “x”.

“x” is a concentration of drug under test. “y” is the response. “a” is the maximum response, and “d” is the minimum response “c” is the inflection point (EC₅₀) for the curve. That is, “y” is halfway between the lower and upper asymptotes when x=c. “b” is the slope-factor or Hill coefficient. The sign of b is positive when the response increases with increasing dose and is negative when the response decreases with increasing dose (inhibition). The data is presented with the qualifiers shown below:

Without/with co- corrector EC50 (μM) <3 +++ ≥3 and <10 ++ ≥10 + Without co- Maximum % corrector activity (%) <50 + ≥50 and <150 ++ ≥150 +++ Maximum % With co-corrector activity (%) <150 + ≥150 and <350 ++ ≥350 +++

TABLE 1 EC50 Maximum % Maximum % (without activity (without activity (with Exam- co-corrector) co-corrector) EC50 (with co- co-corrector) ple # (μM) (%) corrector) (μM) (%) I-1 ++ +++ ++ +++ I-2 ++ +++ +++ +++ I-3 ++ +++ ++ +++ I-4 ++ +++ ++ +++ I-5 +++ +++ +++ +++ I-6 ++ +++ ++ +++ I-7 +++ +++ +++ +++ I-8 ++ +++ ++ +++ I-9 +++ +++ +++ +++ I-10 ++ +++ +++ +++ I-11 +++ +++ +++ +++ I-12 ++ +++ +++ +++ I-13 + + +++ ++ I-14 +++ +++ +++ +++ I-15 +++ +++ +++ +++ I-16 +++ ++ +++ +++ I-17 +++ ++ +++ +++ I-18 +++ +++ +++ +++ I-19 ++ +++ +++ +++ I-20 ++ +++ ++ +++ I-21 ++ +++ ++ +++ I-22 ++ +++ +++ +++ I-23 ++ +++ +++ +++ I-24 ++ +++ +++ +++ I-26 +++ ++ +++ +++ I-27 +++ +++ +++ +++ I-28 +++ +++ +++ +++ I-29 +++ +++ +++ +++ I-30 +++ +++ I-31 +++ ++ +++ +++ I-32 +++ +++ +++ +++ I-33 +++ +++ +++ +++ I-34 +++ +++ +++ +++ I-35 +++ +++ +++ +++ I-36 ++ ++ +++ +++ I-37 ++ ++ ++ +++ I-38 ++ +++ +++ +++ I-39 +++ ++ +++ +++ I-40 +++ +++ +++ +++ I-41 +++ +++ +++ +++ I-42 +++ +++ +++ +++ I-43 +++ ++ +++ +++ I-44 +++ +++ +++ +++ I-45 +++ +++ +++ +++ I-46 ++ +++ +++ +++ I-47 +++ +++ +++ +++ I-48 ++ +++ +++ +++ I-49 +++ +++ +++ +++ I-50 +++ +++ +++ +++ I-51 ++ ++ ++ ++ I-52 +++ +++ +++ +++ I-53 +++ +++ +++ +++ I-54 ++ +++ +++ +++ I-55 +++ +++ +++ +++ I-56 +++ +++ +++ +++ I-57 +++ +++ +++ +++ I-58 +++ +++ +++ +++ I-59 ++ +++ +++ +++ I-60 +++ +++ +++ +++ I-61 +++ +++ +++ +++ I-62 ++ +++ +++ +++ I-63 +++ +++ +++ +++ I-64 +++ +++ +++ +++ I-65 +++ +++ +++ +++ I-66 +++ +++ +++ +++ I-67 +++ +++ +++ +++ I-68 +++ +++ +++ +++ I-69 +++ +++ +++ +++ I-70 +++ +++ +++ +++ I-71 ++ ++ ++ ++ I-72 ++ +++ +++ +++ I-73 ++ +++ +++ +++ I-74 ++ +++ +++ +++ I-75 +++ +++ +++ +++ I-76 ++ +++ +++ +++ I-77 ++ +++ +++ +++ I-78 ++ +++ +++ +++ I-79 ++ +++ +++ +++ I-80 ++ ++ ++ +++ I-81 +++ +++ +++ +++ I-82 +++ +++ +++ +++ I-83 +++ +++ +++ +++ I-84 ++ +++ +++ +++ I-85 ++ ++ ++ +++ I-86 ++ +++ +++ +++ I-87 ++ ++ ++ +++ I-88 +++ +++ +++ +++ I-89 ++ ++ ++ ++ I-90 ++ +++ ++ +++ I-91 ++ ++ ++ +++ I-92 ++ +++ +++ +++ I-93 ++ +++ ++ +++ I-94 +++ +++ +++ +++ I-95 ++ +++ +++ +++ I-96 +++ +++ +++ +++ I-97 +++ +++ +++ +++ I-98 +++ +++ +++ +++ I-99 ++ +++ +++ +++ I-100 +++ +++ +++ +++ I-101 +++ +++ +++ +++ I-102 +++ +++ +++ +++ I-103 ++ +++ ++ +++ I-104 ++ +++ +++ +++ I-105 ++ +++ +++ +++ I-106 ++ +++ +++ +++ I-107 +++ +++ +++ +++ I-108 ++ +++ ++ +++ I-109 ++ +++ +++ +++ I-110 ++ +++ ++ +++ I-111 ++ +++ ++ +++ I-112 ++ +++ ++ +++ I-113 ++ +++ +++ +++ I-114 +++ +++ +++ +++ I-115 ++ +++ +++ +++ I-116 +++ +++ +++ +++ I-117 ++ +++ ++ +++ I-118 +++ +++ +++ +++ I-119 ++ +++ ++ +++ I-120 +++ +++ +++ +++ I-121 ++ +++ ++ +++ I-122 ++ +++ ++ +++ I-123 ++ +++ +++ +++ I-124 +++ +++ +++ +++ I-125 ++ ++ ++ +++ I-126 +++ +++ +++ +++ I-127 ++ +++ +++ +++ I-128 ++ +++ +++ +++ I-129 +++ +++ +++ +++ I-130 ++ +++ ++ +++ I-131 +++ +++ +++ +++ I-132 +++ +++ +++ +++ I-133 +++ +++ +++ +++ I-134 +++ +++ +++ +++ I-135 ++ +++ +++ +++ I-136 +++ +++ +++ +++ I-138 ++ +++ +++ +++ I-139 ++ +++ +++ +++ I-140 +++ +++ +++ +++ I-141 ++ +++ +++ +++ I-142 +++ +++ +++ +++ I-143 ++ ++ +++ +++ I-144 +++ +++ +++ +++ I-145 ++ +++ ++ +++ I-146 +++ +++ +++ +++ I-147 ++ +++ +++ +++ I-148 +++ +++ +++ +++ I-149 +++ +++ +++ +++ I-151 ++ +++ +++ +++ I-152 ++ +++ +++ +++ I-153 ++ +++ +++ +++ I-154 ++ +++ +++ +++ I-155 ++ +++ +++ +++ II-1 ++ ++ ++ +++ II-3 ++ ++ ++ +++ II-4 ++ + ++ ++ II-5 ++ + +++ ++ II-6 ++ ++ ++ ++ II-7 ++ + ++ ++ II-8 ++ ++ ++ ++ II-9 + + ++ ++ II-10 ++ ++ ++ ++ II-11 + + ++ + II-12 ++ + ++ ++ II-13 ++ ++ ++ +++ II-14 ++ + ++ ++ II-15 + + ++ + II-16 ++ + ++ ++ II-17 ++ + ++ ++ II-18 ++ + ++ ++ II-19 ++ ++ ++ ++ II-20 ++ + ++ ++ II-21 ++ + ++ ++ II-22 ++ ++ ++ ++ II-24 ++ + ++ ++ II-25 ++ ++ ++ ++ II-26 + + ++ ++ II-27 + + ++ ++ II-28 ++ + ++ ++ II-29 ++ ++ +++ ++ II-30 ++ + ++ ++ II-31 ++ + ++ ++ II-32 +++ + +++ ++ II-33 ++ ++ ++ +++ II-34 ++ + ++ ++ II-35 ++ ++ ++ ++ II-36 ++ ++ ++ +++ II-37 ++ + ++ ++ II-38 + + ++ ++ II-39 ++ + ++ ++ II-40 ++ ++ ++ ++ II-41 ++ ++ ++ +++ II-42 ++ ++ ++ ++ II-43 ++ ++ ++ ++ II-44 ++ ++ ++ +++ II-45 ++ +++ ++ +++ II-46 ++ ++ ++ +++ II-47 ++ + ++ ++ II-48 ++ ++ ++ +++ II-49 ++ +++ +++ +++ II-50 ++ + ++ ++ II-51 ++ ++ ++ +++ II-52 ++ ++ ++ +++ II-53 ++ ++ ++ +++ II-54 +++ + +++ ++ II-55 + + + + II-56 +++ + +++ ++ II-57 +++ + +++ ++ II-58 +++ + +++ ++ II-59 +++ + +++ ++ II-60 + + + + II-61 + + + + II-62 + + + + II-63 +++ + +++ ++ II-64 +++ + +++ ++ II-65 ++ + ++ ++ II-66 +++ ++ +++ ++ II-67 + + + + II-68 ++ + +++ ++ II-69 +++ ++ +++ +++ II-70 +++ ++ +++ ++ II-72 +++ ++ +++ ++ II-74 + + + + II-75 ++ +++ +++ +++ II-76 +++ + +++ ++ II-77 +++ + +++ ++ II-78 +++ ++ +++ +++ II-79 +++ ++ +++ ++ II-80 + + + + II-81 ++ ++ +++ +++ II-82 + + ++ ++ II-83 ++ ++ ++ ++ II-84 ++ ++ ++ ++ II-85 ++ + ++ ++ II-86 + + ++ ++ II-87 +++ + +++ ++ II-88 ++ ++ +++ +++ II-89 ++ ++ ++ ++ II-90 + + + + II-91 ++ ++ +++ +++ II-92 ++ + +++ ++ II-93 + + +++ + II-94 ++ +++ +++ +++ II-95 +++ +++ +++ +++ II-96 +++ +++ +++ +++ II-97 +++ +++ +++ +++ II-98 +++ +++ +++ +++ II-99 +++ +++ +++ +++ II-100 ++ ++ ++ +++ II-101 +++ + +++ ++ II-102 ++ + +++ ++ II-103 + + +++ + II-104 +++ + +++ ++ II-105 + + +++ + II-106 + + +++ ++ II-107 +++ + +++ ++ II-108 ++ ++ +++ +++ II-109 ++ +++ ++ +++ II-110 ++ +++ +++ +++ II-111 ++ +++ +++ +++ II-112 ++ + +++ ++ II-113 ++ +++ +++ +++ II-114 ++ +++ ++ +++ II-115 ++ +++ +++ +++ II-116 ++ +++ ++ +++ II-117 ++ +++ +++ +++ II-118 ++ +++ +++ +++ II-119 ++ +++ ++ +++ II-120 ++ + ++ ++ II-121 ++ +++ +++ +++ II-122 ++ +++ +++ +++ II-123 ++ +++ ++ +++ II-124 +++ +++ +++ +++ II-125 ++ ++ ++ +++ II-126 ++ ++ ++ +++ II-127 ++ ++ +++ +++ II-128 ++ ++ ++ +++ II-129 +++ +++ +++ +++ II-130 +++ +++ +++ +++ II-131 +++ +++ +++ +++ II-132 +++ +++ +++ +++ II-133 ++ +++ ++ +++ II-134 ++ +++ +++ +++ II-135 ++ +++ ++ +++ II-136 ++ +++ ++ +++ III-3 + + + + III-4 + + + + III-5 + + + + III-6 + + + + III-7 + + ++ ++ III-9 + + + + III-10 + + + + III-11 + + + + III-12 + + ++ + III-13 + + + + III-14 + + + + III-15 + + + + III-16 + + + + III-17 + + + + III-18 + + + + III-19 + + + + III-20 + + + + III-21 + + + + III-22 + + + + III-23 ++ + ++ ++ III-24 + + + + III-25 + + ++ + III-26 + + + + III-27 + + + + III-28 + + + + III-29 + + + + III-30 + + + + III-31 + + + + III-32 + + + + III-33 + + +++ ++ III-34 + + + + III-35 + + ++ ++ III-36 + + + + III-37 + + + + III-38 + + ++ ++ III-39 + + + + III-40 + + + + III-41 + + + + III-42 + + + + III-43 + + + + III-44 + + + + III-45 + + + + III-46 + + + + III-47 + + + + III-48 + + + + III-49 + + ++ ++ III-50 + + + + III-51 + + + + III-52 + + + + III-53 + + + + III-54 + + + + III-55 + + ++ + III-56 ++ ++ ++ +++ III-57 + + + + III-58 ++ + ++ ++ III-59 + + + + III-60 + + + + III-61 + + + + III-62 + + ++ + III-63 + + + + III-64 + + + + III-65 + + + + III-66 + + + + III-67 + + + + III-68 + + + + III-69 + + + + III-70 + + + + III-71 + + ++ ++ III-72 + + + + III-73 + + + + III-74 + + + + III-75 + + + + III-76 + + + + III-77 + + + + III-78 + + + + III-79 + + + + III-80 + + + + III-81 + + + + III-82 + + + + III-83 + + + + III-84 + + + + III-85 + + ++ ++ III-86 ++ ++ +++ ++ III-87 + + + + III-88 + + + + III-89 + + ++ ++ III-90 + + + + III-91 + + + + III-92 + + + + III-93 + + ++ ++ III-94 + + ++ ++ III-95 + + + + III-96 + + + + III-97 + + + + III-98 + + + + III-99 ++ ++ ++ +++ III-100 + + ++ + III-101 + + + + III-102 + + + + III-103 + + ++ ++ III-105 + + + + III-106 + + + + III-107 ++ ++ ++ +++ III-108 ++ ++ ++ ++ III-109 + + + + III-110 + + + + III-111 + + ++ + III-112 ++ + ++ ++ III-113 + + +++ ++ III-114 ++ + +++ ++ III-115 +++ + +++ ++ III-116 + + + + III-117 ++ + +++ ++ III-118 + + + + III-119 + + ++ + III-120 + + + + III-121 + + + + III-122 + + + + III-123 + + ++ ++ III-124 + + + + III-125 ++ + ++ ++ III-126 + + + + III-127 + + + + III-128 ++ + ++ ++ III-129 + + ++ ++ III-130 + + + + III-131 + + + + III-132 + + ++ ++ III-133 + + ++ ++ III-134 + + + + III-135 + + + + III-136 + + + + III-137 + + + + III-138 ++ + ++ ++ III-139 +++ + +++ ++ III-140 + + + + III-141 + + + + III-142 ++ + ++ ++ III-143 + + + + III-144 + + ++ ++ III-145 ++ + ++ ++ III-146 + + ++ + III-147 ++ + ++ ++ III-148 +++ +++ +++ +++ III-149 + + +++ + III-150 + + + + III-151 + + + + III-152 ++ + ++ ++ III-153 + + + + III-154 +++ +++ +++ +++ III-155 ++ + ++ ++ III-156 ++ ++ +++ ++ III-157 + + ++ ++ III-158 ++ ++ ++ ++ III-159 ++ +++ ++ +++ III-160 ++ ++ ++ +++ III-161 ++ + ++ ++ III-162 ++ ++ ++ +++ III-163 + + ++ ++ III-164 +++ ++ +++ +++ III-165 ++ ++ +++ ++ III-166 +++ ++ +++ ++ III-167 ++ + +++ ++ III-168 ++ ++ ++ +++ III-169 ++ +++ +++ +++ III-170 +++ ++ +++ +++ III-171 ++ ++ ++ +++ III-172 ++ + +++ ++ III-173 ++ ++ ++ +++ III-174 + + + + III-175 + + + + III-176 + + + + III-177 + + ++ ++ III-178 ++ + ++ ++ III-179 + + + + III-180 + + + + III-181 + + ++ ++ III-182 +++ ++ +++ ++ III-183 + + ++ ++ III-184 ++ ++ ++ ++ III-185 ++ + ++ ++ III-186 + + + + III-187 + + + + III-188 + + ++ +

The data provided in the present application demonstrate that the compounds of the invention demonstrate activity in vitro, and may be useful in vivo in the treatment of cystic fibrosis.

Further benefits of Applicants' invention will be apparent to one skilled in the art from reading this patent application.

It is to be understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, or methods, or any combination of such changes and modifications of use of the invention, may be made without departing from the spirit and scope thereof. 

What is claimed:
 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof,

wherein A¹ is selected from the group consisting of

X¹ is N or C(R^(2A)); X² is N or C(R^(2B)); X³ is N or C(R^(2C)); X⁴ is N or C(R^(2D)); R¹ is selected from the group consisting of hydrogen, OH, CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R¹ C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of R⁷, OR⁷, SR⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I; one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; or two of R^(2A), R^(2B), R^(2C), and R^(2D) on adjacent carbons form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein the phenyl, 5-6 membered heteroaryl, C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁸, OR⁸, C(O)R⁸, OC(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R⁹, OR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I; R⁴ is selected from the group consisting of hydrogen and C₁-C₆ alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹⁰, OR¹⁰, SR¹⁰, NHR¹⁰, N(R¹⁰)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I; R^(5A), R^(5B), R^(5C), and R^(5D) are each independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R^(5A), R^(5B), R^(5C), and R^(5D) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5A), R^(5B), R^(5C), and R^(5D) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; or R^(5A) and R^(5B), together with the carbon atom to which they are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic cycloalkyl and the 4-7 membered monocyclic heterocycle are each optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and R^(5C) and R^(5D) are each independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R^(5C) and R^(5D) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5C) and R^(5D) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; or R^(5A) and R^(5B) are each independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R^(5A) and R^(5B) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₁-C₆ alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, 4-12 membered heterocyclyl, C₁-C₆ thioalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R^(5A) and R^(5B) 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; and R^(5C) and R^(5D), together with the carbon atom to which they are attached, form a C₃-C₇ monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle; wherein the C₃-C₇ monocyclic cycloalkyl and the 4-7 membered monocyclic heterocycle are each optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C(O)OH, NH₂, OH, oxo, CN, NO₂, F, Cl, Br and I; R^(6A), R^(6B), R^(6C), and R^(6D) are each independently hydrogen; R⁷, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁷ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, oxo, OH, CN, NO₂, F, Cl, Br and I; R⁸, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹¹, OR¹¹, C(O)OR¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein each R⁸ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹², OR¹², C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I; R⁹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R¹³, OR¹³, SR¹³, C(O)R¹³,NHR¹³, N(R¹³)₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴, OR¹⁴, C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴, SO₂R¹⁴, NHR¹⁴, N(R¹⁴)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I; R¹⁰, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹⁰ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹⁰ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; R¹¹, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹ C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I; R¹², at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹² C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹² C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I; R¹³, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; and R¹⁴, at each occurrence, is independently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I; with the proviso that R³ is not methyl; with the proviso that, when R^(2A), R^(2B), R^(2C), and R^(2D) are each hydrogen, R¹ is not hydrogen; with the proviso that, when R³ is naphthyl, R^(2C) is not 4-(1-methylethyl)phenoxy; and with the proviso that, when R¹ is C₁-alkyl, R³ is not 3-pyridinyl or 4-cyanobenzyl.
 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X¹ is C(R^(2A)); X² is C(R^(2B)); X³ is C(R^(2C)); and X⁴ is C(R^(2D)).
 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A¹ is


4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A¹ is


5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A¹ is


6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein one of R^(2A), R^(2B), R^(2C), and R^(2D) is hydrogen, and the remaining are independently selected from the group consisting of hydrogen, R⁸, OR⁸, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)OH, OH, CN, F, Cl, and Br.
 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen or C₁-C₆ alkyl; which is unsubstituted.
 8. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1R)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 1-benzyl-4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 1-benzyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 1-ethyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1R)-8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1S)-8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-N-(2,2-difluoro-2H-1,3-benzodioxole-4-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-1-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (6S)-6-methyl-N-(naphthalene-1-sulfonyl)-7,8-dihydro-2H,6H-indeno[4,5-d][1,3]dioxole-6-carboxamide; (6R)-6-methyl-N-(naphthalene-1-sulfonyl)-7,8-dihydro-2H,6H-indeno[4,5-d][1,3]dioxole-6-carboxamide; (1S)-6-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-6-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(naphthalene-1-sulfonyl)-6,7,8,9-tetrahydro-2H-naphtho[1,2-d][1,3]dioxole-6-carboxamide; (1S)-7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-1-ethyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-(cyclopropylmethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 1-butyl-4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(8-hydroxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 8-bromo-5-ethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-N-(naphthalene-1-sulfonyl)-1-[6-(trifluoromethyl)pyridin-2-yl]methyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-[(6-chloropyridin-3-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-[(6-methoxypyridin-2-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(5-chloronaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 8-bromo-N-(naphthalene-1-sulfonyl)-5-[(propan-2-yl)oxy]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-bromo-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-1-ethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(1-benzothiophene-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 8-bromo-5-(2-methoxyethoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1S)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1R)-8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1S)-4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-7-ethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-N-(naphthalene-1-sulfonyl)-7-[(propan-2-yl)oxy]-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-7-(cyclopropylmethoxy)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 8-bromo-5-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-methoxy-8-(4-methylphenyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-bromo-7-(difluoromethoxy)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1R)-8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1S)-5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1R)-5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1S)-8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1R)-8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-1-ethyl-N-(1-methyl-1H-indole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 5-methoxy-8-(2-methylpropyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-methoxy-5-(2-methylpropyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-cyclobutyl-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-chloro-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1S)-4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 5,8-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-1-ethyl-N-(1-methyl-1H-indole-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 7-methoxy-4-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-N-(imidazo[1,2-a]pyridine-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 2-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; (1S)-4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 8-cyclobutyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 7-cyclobutyl-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 5-cyclopropyl-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1S)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-7-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-7-methoxy-N-(2-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; (1R)-4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-N-(5-hydroxynaphthalene-1-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; (7S)-2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; (7R)-2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; (1R)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide; 4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide; 4-chloro-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide; 4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide; 2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; (8S)-4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide; (8R)-4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide; (1S)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (8R)-4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide; (8S)-4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoline-8-carboxamide; (1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 7-methoxy-N-(naphthalene-1-sulfonyl)-4-(prop-1-en-2-yl)-2,3-dihydro-1H-indene-1-carboxamide; 4-(2-hydroxypropan-2-yl)-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; 4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 2-cyclobutyl-5-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; 4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 2-cyclobutyl-5-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; 2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; 7-methoxy-N-(naphthalene-1-sulfonyl)-4-(oxolan-2-yl)-2,3-dihydro-1H-indene-1-carboxamide; 7-methoxy-4-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 7-methoxy-4-(2-methylpropyl)-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (7S)-2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; (7R)-2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; (7S)-2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; (7R)-2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; (7S)-2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; (7R)-2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; 7-methoxy-3,3-dimethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (7R)-2-cyclobutyl-5-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; N-(benzenesulfonyl)-4-chloro-1-methyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-6-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)-6-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2-chlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-methoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5,6-dimethoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-chloro-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 6-fluoro-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1R)-5-methoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1S)—N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 6,7-dimethoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-2-carboxamide; (1R)—N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1S)-6-methoxy-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 7-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4,5-difluoro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 1,5-dimethyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-ethylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2-ethylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(3-chlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(4-chlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2-fluorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-4-chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(2-nitrobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-(3,6-dihydro-2H-pyran-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-cyclobutyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-phenyl-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-[2-(trifluoromethyl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; N-(2-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(2-bromobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-[(propan-2-yl)oxy]-2,3-dihydro-1H-indene-1-carboxamide; 7-bromo-4-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-(2-methoxypyridin-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 5-methoxy-N-(quinoline-8-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; (1R)-5-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-5-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; (1S)-4-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(naphthalene-1-sulfonyl)-1-[(pyrrolidin-1-yl)methyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-2-carboxamide; 1-methyl-N-(naphthalene-1-sulfonyl)-6-(trifluoromethoxy)-2,3-dihydro-1H-indene-1-carboxamide; 8-bromo-5-hydroxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5,6-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-amide; N-(naphthalene-1-sulfonyl)-2,3,7,8,9,10-hexahydronaphtho[1,2-b][1,4]dioxine-7-carboxamide; 6,7-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-N-(2-chlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(2-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-[5-methyl-2-(propan-2-yl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-[3-chloro-2-(methoxymethyl)benzene-1-sulfonyl]-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(2-fluorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(2-phenoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-[2-(trifluoromethoxy)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-[2-(difluoromethoxy)benzene-1-sulfonyl]-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2,5-dimethylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-[2-(2-methoxyethoxy)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; N-([1,1′-biphenyl]-2-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(benzenesulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; N-(2,1,3-benzothiadiazole-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(naphthalene-1-sulfonyl)-1-[(oxolan-3-yl)methyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(naphthalene-1-sulfonyl)-1-[2-(1H-pyrazol-1-yl)ethyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-[(5-methoxypyridin-2-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-[(2-methoxypyridin-4-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(naphthalene-1-sulfonyl)-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2,3-dihydro-1,4-benzodioxine-5-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(4-bromonaphthalene-1-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(4-fluoronaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(5-bromonaphthalene-1-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(5,6,7,8-tetrahydronaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(3,4-dihydroquinoline-1(2H)-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-(hydroxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-cyclobutyl-N-(4-cyclobutylnaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-cyclobutyl-N-(5-cyclobutylnaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 8-bromo-5-(cyclohexylmethoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-bromo-5-[(3-methoxyphenyl)methoxy]-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-bromo-5-[(3-methoxyphenyl)methoxy]-N-[(3-methoxyphenyl)methyl]-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; ethyl({4-bromo-5-[(naphthalene-1-sulfonyl)carbamoyl]-5,6,7,8-tetrahydronaphthalen-1-yl}oxy)acetate; 8-bromo-5-(cyclopentyloxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-(benzyloxy)-8-bromo-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; N-benzyl-5-(benzyloxy)-8-bromo-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-bromo-N-(naphthalene-1-sulfonyl)-5-[(oxetan-3-yl)oxy]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-bromo-N-(naphthalene-1-sulfonyl)-5-[(oxan-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-bromo-5-(2-hydroxy-2-methylpropoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 6,8-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-methoxy-N-(naphthalene-1-sulfonyl)-8-[4-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-methoxy-N-(naphthalene-1-sulfonyl)-8-[(E)-2-phenylethenyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-(2,2-difluoro-2H-1,3-benzodioxol-4-yl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-(2-fluoro-4-methylphenyl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-methoxy-N-(naphthalene-1-sulfonyl)-8-(2-phenoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; N-(3-bromo-2-methylbenzene-1-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(3-fluoro-2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-[2-(methoxymethyl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2,3-difluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-[2-(2,2-difluoroethoxy)benzene-1-sulfonyl]-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(quinoxaline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(3-chloro-2-fluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2,3-dichlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(1-methyl-1H-indole-3-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 5-[2-(1,3-dioxan-2-yl)ethyl]-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-cyano-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 5-cyano-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-N-(3-cyclobutyl-2-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(isoquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; 8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-bromo-7-methoxy-N-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-N-(8-fluoroquinoline-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 7-ethyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; 8-methoxy-N-(naphthalene-1-sulfonyl)-5-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-methoxy-N-(naphthalene-1-sulfonyl)-5-[(E)-2-phenylethenyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-methoxy-8-(6-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-bromo-N-(2-ethoxyquinoline-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 8-methoxy-N-(naphthalene-1-sulfonyl)-5-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-1-ethyl-N-[2-methyl-3-(piperidin-1-yl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-[3-(3,3-difluoroazetidin-1-yl)-2-methylbenzene-1-sulfonyl]-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-[3-(3,3-difluoropyrrolidin-1-yl)-2-methylbenzene-1-sulfonyl]-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 5-chloro-8-hydroxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-methoxy-N-(naphthalene-1-sulfonyl)-8-[6-(trifluoromethyl)pyridin-3-yl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-(3,6-dihydro-2H-pyran-4-yl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-(6-cyclopropylpyridin-3-yl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-bromo-7-methoxy-N-[2-(propan-2-yl)quinoline-5-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-7-methoxy-N-(5-methoxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; methyl 7-methoxy-1-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-indene-4-carboxylate; methyl 5-[(4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]naphthalene-1-carboxylate; 5-chloro-8-[2-(morpholin-4-yl)ethoxy]-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-1-methyl-N-(phenylmethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2-methoxyethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(propane-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 8-methoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide; 5-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide; 4-methoxy-N-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(2-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(5-methylpyridine-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(oxane-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(3-methoxypropane-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(2-methoxyethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(propane-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(5-methylpyridine-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(4-hydroxybenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(phenylmethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(6-hydroxynaphthalene-2-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(4-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(5-acetamido-1,3,4-thiadiazole-2-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-[5-methyl-2-(propan-2-yl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; N-[4-(methanesulfonyl)benzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(3-nitrobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(4-chloro-3-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(6-chloro-1,1-dioxo-1,2-dihydro-1λ⁶,2,4-benzothiadiazine-7-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(2-methyl-5-nitrobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(4-acetamido-2-methylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(4-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(4-chloro-2-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(3-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-[4-(3-oxobutanamido)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; N-(2,4-dichlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(4-amino-2-chloro-5-methylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(2-chloro-5-methylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(2-chloro-5-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(4-acetamidobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(4-acetamido-2-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(4-butanamidobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(2,4-dihydroxy-6-methylpyrimidine-5-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(4-cyanobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(2-oxo-2H-1-benzopyran-6-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; ethyl 4-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]benzoate; N-(2,4-dimethyl-3-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-{2-chloro-5-[(2,6-dimethylphenyl)carbamoyl]-4-hydroxybenzene-1-sulfonyl}-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-[1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-[3-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}carbamoyl)-4-methoxybenzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(6-ethoxy-1,3-benzothiazole-2-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(4-hexanoylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-[4-(4-{2-[(1S)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazin-1-yl)benzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; propan-2-yl 2-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]benzoate; N-{4-[(3-hydroxy-3-methylbutyl)amino]-3-nitrobenzene-1-sulfonyl}-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-[2-chloro-5-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)benzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-{7-[(4-chlorophenyl)methyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonyl}-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(9-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purine-8-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-{4-[(dimethylamino)methyl]benzene-1-sulfonyl}-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(2-cyano-3-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(4-hydroxy-3-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(3-cyanobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(5-bromopyridine-3-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(6-hydroxypyridine-3-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(4-cyano-1,3-dimethyl-1H-pyrazole-5-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; tert-butyl 5-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-1,3-dimethyl-1H-pyrazole-4-carboxylate; N-[4-(hydroxymethyl)-1,3-dimethyl-1H-pyrazole-5-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(3-chloro-2-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(2,6-difluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4,5-dimethoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(5-chloro-2-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(2,5-difluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(2-chloro-5-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(2,6-dichlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(2,4-difluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-[1-(2-methoxyethyl)-1H-pyrazole-4-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; N-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(2,4-dimethyl-1,3-thiazole-5-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(pyridine-3-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 2-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-N,N-dimethylpyridine-3-carboxamide; N-(2-cyanopyridine-3-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-methoxy-N-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-(6-methoxypyridin-3-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-[6-(piperidin-1-yl)pyridin-3-yl]-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(2-methylpyridin-3-yl)-2,3-dihydro-1H-indene-1-carboxamide; 4-(6-fluoropyridin-3-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-[6-(dimethylamino)pyridin-3-yl]-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-(5-fluoropyridin-3-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(5-methylpyridin-3-yl)-2,3-dihydro-1H-indene-1-carboxamide; 4-(2-fluoropyridin-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-(3-fluoropyridin-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(3-methylpyridin-4-yl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(2-methylpyridin-4-yl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(1H-pyrazol-4-yl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(1H-pyrazol-5-yl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(thiophen-3-yl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(3-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(5-methylfuran-2-yl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(2-methylfuran-3-yl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-methylbenzene-1-sulfonyl)-4-(1-methyl-1H-pyrazol-5-yl)-2,3-dihydro-1H-indene-1-carboxamide; (1R)—N-(2-aminopyridine-3-sulfonyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide; N-(6-aminopyridine-2-sulfonyl)-1,5-dimethyl-2,3-dihydro-1H-indene-1-carboxamide; (1R)—N-(6-aminopyridine-2-sulfonyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide; N-(6-aminopyridine-2-sulfonyl)-8-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-N-(naphthalene-1-sulfonyl)-1-[2-(pyrrolidin-1-yl)ethyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2,4-dichlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2,4-dimethylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2,6-difluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2,5-dichlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(3-chlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2-chloro-5-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2-cyanobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2,6-dimethoxybenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-[2-(trifluoromethyl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2-chloro-6-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(4-chlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-[2-methyl-6-(trifluoromethyl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2-cyano-3-fluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(1-methylcyclopropane-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-([1,1′-biphenyl]-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-{4-[(dimethylamino)methyl]benzene-1-sulfonyl}-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(2-chloropyridine-3-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(quinoline-6-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 2-[(4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-N,N-dimethylpyridine-3-carboxamide; 4-chloro-N-(cyclohexanesulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-{4-[4-(propan-2-yl)piperazin-1-yl]pyridine-3-sulfonyl}-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-{2-[2-(piperidin-1-yl)ethoxy]benzene-1-sulfonyl}-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(4-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(phenylmethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindole-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(4-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(4-phenoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(3-cyanobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-(1H-pyrazole-3-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 3-{4-chloro-1-[naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-inden-1-yl}propanoic acid; 4-chloro-N-(naphthalene-1-sulfonyl)-1-[(pyridin-2-yl)methyl]-2,3-dihydro-1H-indene-1-carboxamide; 5-methoxy-N-(naphthalene-1-sulfonyl)-8[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; methyl 2-chloro-6-[(4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]benzoate; 4-chloro-1-ethyl-N-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-7-hydroxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 5-methoxy-8-(morpholin-4-yl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-methoxy-N-(naphthalene-1-sulfonyl)-8-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-1-(cyanomethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-N-(3-chloro-2-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide; 8-chloro-1-cyano-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-bromo-7-methoxy-N-(2-methoxypyridine-3-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(2-aminopyridine-3-sulfonyl)-4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; N-(6-aminopyridine-2-sulfonyl)-4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-N-(4-ethoxynaphthalene-1-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-7-methoxy-N-(4-methoxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-bromo-7-methoxy-N-([1,2,4]triazolo[4,3-a]pyridine-8-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 8-methoxy-N-(naphthalene-1-sulfonyl)-5-(pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 5-(6-cyclopropylpyridin-3-yl)-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-methoxy-N-(naphthalene-1-sulfonyl)-5-(pyridin-4-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-methoxy-5-(6-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 7-methoxy-4-(pyrimidin-5-yl)-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 4-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 8-methoxy-5-(4-methylphenyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 8-methoxy-N-(naphthalene-1-sulfonyl)-5-[6-(trifluoromethyl)pyridin-3-yl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 4-chloro-1-ethyl-N-[2-methyl-3-(morpholin-4-yl)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-1-carboxamide; 4-chloro-1-ethyl-N-{3-[(2-methoxyethyl)(methyl)amino]-2-methylbenzene-1-sulfonyl}-2,3-dihydro-1H-indene-1-carboxamide; 5-methoxy-N-(naphthalene-1-sulfonyl)-8-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; 2,3-dimethoxy-N-(2-methylbenzene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; N-(2-methylbenzene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; 2,3-dimethoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; 2-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide; 2-chloro-6-[(4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]benzoic acid; 1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxamide; 5-[(4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]naphthalene-1-carboxylic acid; 7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 7-methoxy-1-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-indene-4-carboxylic acid; methyl 7-methoxy-3-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-indene-4-carboxylate; 4-(hydroxymethyl)-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide; 7-methoxy-N⁴-methyl-N¹-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1,4-dicarboxamide; 7-methoxy-N⁴,N⁴-dimethyl-N¹-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1,4-dicarboxamide; and 7-methoxy-N-(naphthalene-1-sulfonyl)-4-[pyrrolidin-1-yl)methyl]-2,3-dihydro-1H-indene-1-carboxamide.
 9. (1S)-4-Chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide, or a pharmaceutically acceptable salt thereof.
 10. (1R)-4-Chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide, or a pharmaceutically acceptable salt thereof.
 11. (1S)-4-Bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide, or a pharmaceutically acceptable salt thereof.
 12. (1R)-4-Bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide, or a pharmaceutically acceptable salt thereof.
 13. (1S)-7-Methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide, or a pharmaceutically acceptable salt thereof.
 14. (1R)-7-Methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxamide, or a pharmaceutically acceptable salt thereof.
 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
 16. A compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in medicine.
 17. A compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of cystic fibrosis.
 18. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, one potentiator, and one or more additional correctors.
 19. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.
 20. The pharmaceutical composition of claim 19, wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers.
 21. The pharmaceutical composition of claim 19, wherein the additional therapeutic agents are CFTR modulators. 